- Email: [email protected]
Chapter 7. Pulmonary and Antiallergy Agents
S e c t i o n I1 Editor:
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Pharinacodynamic A g e n t s
W i l l i a m T . Comer, B r i s t o l - M y e r s R e s e a r c h a nd D e ve lopm e nt 345 P a r k Avenue, N e w York, New York 10154 Chapter 7 .
Pulmonary and A n t i a l l e r g y A ge nts
J o h n D . C a t t an d E l i z a b e t h G i l l e s p i e , B r i s t o l - M y e r s P r e c l i n i c a l C a r d i o v a s c u l a r R e s e a r c h , E v a n s v i l l e , I n d i a n a 47721 I n t r o d u c t i o n - Compounds o f s p e c i f i c i n t e r e s t w i t h r e s p e c t t o a l l e r g y and a s t h m a a r e d i s c u s s e d i n some o f t h e f o l l o w i n g s e c t i o n s . R e s e a r c h on a r a c h i d o n i c a c i d and i t s v a r i o u s m e t a b o l i t e s proceeded a t a b r i s k pace i n 1 9 8 2 . S e v e r a l g e n e r a l reviews d e a l i n g w i t h c y c l o o x y g e n a s e a n d / o r l i p o x y genase p r o d u c t s have appeared.'-5 However, u n t i l c l i n i c a l d a t a a p p e a r on agents a f f e c t i n g arachidonic a c i d m e t a b o l i t e s , whether i n i n h i b i t i n g s y n t h e s i s o f l e u k o t r i e n e s , b l o c k i n g r e l e a s e o r e f f e c t s o f SRS, o r i n h i b i t i n g lipoxygenase products, t h e c l i n i c a l b e n e f i t of t h i s type of agent remains u n c l e a r . Slow R e a c t i n g S u b s t a n c e (SRS) an d L e i i k o t r i e n e s (LTs) - S e v e r a l s i g n i f i c a n t p a p e r s h a v e a p p e a r e d wh i ch d e s c r i b e new s y n t h e t i c p r e p a r a t i o n s o f leukotrienes. A s t e r e o s p e c i f i c s y n t h e s i s of l e u k o t r i e n e s from 2-deoxyD - r i b o s e h a s b e e n d e s c r i b e d , 6 and LTC4, LTD4, a n d LTE4 h a v e b e e n p r e p a r e d from 5-HPETE by a s t e r e o s e l e c t i v e , b i o m i m e t i c r o u t e . Eight synthetic i s o m e r s o f LTD4 h a v e b e e n s y n t h e s i z e d a nd compared. Only t h e 5 S , 6 R , 7 , 9 trans,ll,l4-cis i s o m e r was i d e n t i c a l t o b i o l o g i c a l l y - g e n e r a t e d g u i n e a p i g LTD4 i n a l l r e s p e c t s . ' I n a n o t h e r s t u d y i n v o l v i n g a n a l o g s o f LTC4 and LTD,, i t was f o u n d t h a t t h e 5-OH and c a r b o x y l g r o u p s were e s s e n t i a l f o r SRS a c t i v i t y b u t v a r i a t i o n o f t h e p e p t i d e m o i e t y o n l y p a r t i a l l y decreased a ~ t i v i t y . S ~ u l f o n e s o f L I T 4 , LTD4 and LTE4 h a v e b e e n p r e p a r e d from t h e c o r r e s p o n d i n g LTs. l o They were b i o l o g i c a l l y s i m i l a r t o t h e LTs with about half t h e potency. l1 Ll'C4 a d m i n i s t e r e d by a e r o s o l was shown t o c a u s e b r o n c h o c o n s t r i c t i o n i n n o r m a l human v o l u n t e e r s > 2 w h i l e i n c u l t u r e s o f human l u n g c e l l s b o t h LTC, a n d LTD413 were f o u n d t o i n c r e a s e mucus p r o d u c t i o n . I n monk e y s , LTC4 c a u s e d a d e c r e a s e i n p u l m o n a r y c o m p l i a n c e , c o n t r a c t e d i s o l a t e d t r a c h e a l s p i r a l s and r e d u c e d c i r c u l a t i n g l e u k o c y t e s . l 4 S t u d i e s i n g u i n e a p i g s h a v e a t t e m p t e d t o e l u c i d a t e t h e mechanisms o f a c t i o n s of t h e LTs. In g u i n e a p i g t r a c h e a l p r e p a r a t i o n s , LTC4 c a u s e d a d e c r e a s e i n CAMP b u t d i d n o t a l t e r cGMP. The c o n t r a c t i o n s c a u s e d b y LTC4 i n t h i s s t u d y were n o t a l t e r e d by i n d o m e t h a c i n . l 5 I n a n o t h e r s t u d y , LTC4 and LTD4 were shown t o r e l e a s e TXA2 and p r o s t a g l a n d i n - l i k e m a t e r i a l from g u i n e a p i g l u n g a nd induce c o n t r a c t i o n i n parenchymal s t r i p s . Both t h e s e a c t i o n s were i n h i b i t e d by i m i d a z o l e , a t h r o mb o x an e s y n t h e t a s e i n h i b i t o r . l 6
SRS A n t a g o n i s t s - S e v e r a l compounds o t h e r t h a n FPL 55712 a n d i t s a n a l o g s The bromo d e r i v a t i v e 1 s e l e c t i v e l y a n t a g o n i z e t h e a c t i o n s o f SRS. inhibited the SRS-induced contractions of guinea pig ile um " (ICs,-, = 5 0 PM)~; w h i l e t h e f u s e d r i n g a n a l o g 2 i n h i b i t e d w i t h a n BL5255 ( 3 ) a n t a g o n i z e d SRS and LTD4-induced c o n t r a c t i o n IC5o o f 5 pM.
ANNUAL REPORTS I N MEDICINAL C H F N I S T R Y 4 I I
Copyright D 1983 by Academ~cPress. Ine All righis of reproductiontn any form r e w v e d . ISBN 0- I20405 I 8 4
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of guinea pig tracheal rings over the concentration range 10-6-10-4M.l9 At the higher concentrations, histamine- and methacholine-induced contractions were also inhibited. The propenamides k and 5 are representative of a series that was shown to antagonize SRS actions on guinea pig ileum at 1 0 - ~ ~ . 2 O ' ~ 1
coo"
4
A =SJHCOCH=CHCOOH
5
A
z
OH
6
R e H
7 R=Me r;r Leukotriene Synthesis Inhibitors - The pyrrole prostacyclin analog U-60,257 (6) and its methyl ester U-56,467 (1)inhibited LTC4 and LTD4 synthesis induced by calcium ionophore in human polymorphonuclear leukocytes.22 U-60,257 did not inhibit formation of 12-HETE in human platelets but did inhibit antigen-induced bronchopulmonary changes in monkey and guinea pig in v ~ v o .Ro~ 21-7634 ~ ( S ) inhibited the synthesis 0-
0
8 -
9 -
of SRS in rat peritoneal mast cells and TXA2 synthesis in perfused guinea pig lung at similar concentrations but did not inhibit TXA2 production induced by direct perfusion of SRS into the lung.24 A preliminary report indicated that the urea 9 is a selective inhibitor of LTCd synthesis.25 Diethylcarbamazine inhibited LTB4 and C4 biosynthesis in calcium ionophore stimulated mouse mastocytoma cells, while cyclooxygenase and lipoxygenase activity were unaffected.26 Lipoxygenase Inhibitors - The non-steroidal anti-inflammatory agent benoxaprofen, previously reported to selectively inhibit lipoxygenase at therapeutic levels, failed to be efficacious in aspirin-sensitive patient^.^' In in vitro studies, benoxaprofen inhibited SRS release from human and guinea pig lung following antigen challenge and reduced SRS release in vivo but did not antagonize the actions of SRS.28 Nafazatrom (Bay g 6575) inhibited tumor cell lipoxygenase activity but not cyclooxygenase product formation at pM concentrations.29 The 5,6-methanoleukotriene A4, (KCN-TEI-6173, E),a stable LT, inhibited 5-lipoxygen-
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ase synthesis, (IDSo = 18 pM) and did not inhibit prostaglandin (cyclooxygenase) synthesis at concentrations up to 150 The acetylenic
CH J,COOH
CSHll
5,6-dehydroarachidonic acid, 11, inhibited 5-lipoxygenase in RBL extracts (K = 15 pM) but was much less active in intact cells due to metabolism. The flavonoid baicalein. l2, selectively inhibited platelet lipoxygenase (IC50 = 0.12 VM).~* '
12 -
Mediator Release Inhibitors - The imidazopyridine, 3-deaza-SIBA (E),at concentrations of approximately 10-4M, inhibited IgE-mediated histamine release from rat basophilic leukemia cells and histamine release from rat peritoneal mast cells induced by compound 48/80, calcium ionophore, and ATP.33
hie
14 R = CH,CH,OH 1 5 R-H -
16 -
In asthmatic patients, tiaramide improved lung function and reduced the need for inhaled beta agonist.34 Tiaramide (2,RHC 2592-A) and its major metabolite, desethanol tiaramide (2,RHC 3281) inhibited IgE- and IgG-mediated histamine release from rat peritoneal mast cells and guinea pig lung slices, respectively. 3 5 In other studies, tiaramide inhibited formation of TXA2 and antagonized bronchoconstrictor mediators with selectivity for PGF2a and SRS in guinea pigs. The hydrazine derivative 16 had activity 3 x DSCG in the rat PCA test and also inhibited histamine release from rat mast The pyrimidine urea 17 inhibited IgE-mediated histamine release from human basophils, as well as the PCA in rats.39 The oxamate 18 (MTB) inhibited IgE-mediated histamine release from rat peritoneal cells and the PCA reaction in rats and guinea pigs.4o The orally active antiallergy compound traxanox sodium inhibited histamine release from rat mast cells induced by antigen or compound 48/80 but had only marginal effects on calcium ionophore-induced release. The azaxanthine 19 - (M&B 22,948) was 30 x DSCG as a mediator release inhibitor and was
*'
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effective against exercise-induced but not histamine-induced bronchoconstriction (fall in FEV,) in asthmatic patients.42 TR 2855, a chromone that inhibits antigen-induced release of histamine and SRS from passively sensitized human lung, relaxed human bronchial and guinea pig tracheal muscle and caused bronchodilation in guinea pigs. 43 p-Adrenoceptor Agonists - Clinical trials in asthmatic patients of the p2-agonists terbutaline, albuterol, fenoterol and carbuterol failed to differentiate between the group in that all four compounds showed the side effects of tremor and t a c h y ~ a r d i a . ~ ~ Another ' ~ ~ study with two new highly selective p2-agonists D-2343 (20) and QH25 (21) also failed to separate bronchodilator and tremorigenic effects and concluded that the p2-adrenoceptor in bronchial muscle and skeletal muscle are the same.46 D-2343 and QH25 were found to have a potency of 0.2 x terbutaline and 12 x albuterol, respectively.47 Although clenbuterol showed a selectivity for p2-adrenoceptorsY its high agonist potency was attributed to high affinity for the fi-adrenoceptor rather than efficient adrenoceptor activation.48 In patients with reversible airway obstruction, procaterol exhibited a dramatic bronchodilator effect with duration up to 12 h.49 An FDA study commission has concluded from recent animal studies that cardiac toxicity of p-adrenoceptor agonists was enhanced by concomitant administration of methyl xanthines There are , however , conflicting reports; in a study of albuterol and theophylline in ~ o m b i n a t i o n and ~ ~ a second study of theophylline and terbutaline results indicated that low-dose bronchodilator/theophylline combinations gave better bronchodilation with fewer tremors and tachycardia than a high dose of either drug alone.52 In a different context the combination of fenoterol and ipratropium, an anticholinergic bronchodilator (see below), achieved bronchodilatory efficacy similar to high doses of fenoterol alone but with fewer side effects.13
.
The activity of the terbutaline analog KWD 2131 (22) in bronchial allergen challenge was shown to be due entirely to bronchodilation with 20 -
B
C
R
H
OH
H
CHfQ
I-\
H
22 23 -
-
A
OMe H
OH
H
OH
OH
OCONMe,
H
OCONMeo
H
Chap. 7
Pulmonary and Antiallergy
Catt, Gillespie
2
no antiallergic effect being observed.'* The terbutaline pro-drugs KWD 2183 (g) and D 2438 (2)were potent bronchodilators in guinea pigs and maintained therapeutic plasma levels in dogs for 23 h and 12 h respectively. These compounds caused a significantly smaller increase in heart rate than did terbutaline.55 The bronchodilatory activity of 26 was found to be in the 2-isomer as was the case for its parent TMQ (g).56 The g-methyl derivatives, 27 and 2 8 , were 15- and 4-times more selective for p2-adrenoceptors over E-adrenoceptors than TMQ. 57
!L!il%h
bMe
25
OH
H
H
H
26
H
OH
H
H
27
OH
H
Me
H
threo
28
OH
H
H
Me
erythro
A study of the four drugs isoprenaline, terbutaline, albuterol, and soterenol as to the effect of N-aralkyl substitution indicated that this substitution increased 8 2 - and al-adrenoceptor selectivity with the 8 2 effect most noticeable with soterenol.5s
Calcium-Antagonist - Verapamil and nifedipine were found to inhibit exercise- induced b ronchoconstric tion in asthmatic subjectsP9 while in animal studies nifedipine was found to inhibit bronchoconstriction induced by histamine in both guinea pigs60 and dogs.61 In an in vitro study, methoxyverapamil (D-600) inhibited concanavalin A-induced histamine release and calcium ion influx in rat peritoneal mast cells but did not inhibit compound 48/80-induced histamine release.62 Verapamil inhibited experimental anaphylaxis in guinea pig tracheal smooth muscle but failed to inhibit histamine release from tracheal mast cells.63 Nifedipine inhibited the PCA reaction in rats with a potency 50 x DSCG but did not inhibit skin reactions induced by histamine or methacholine. Corticosteroids - The mechanism whereby anti-inflammatory steroids inhibit IgE-mediated histamine release from human leukocytes was explored. It was shown that overnight culture of cells with dexamethasone did not alter either total or occupied Fc receptor number and indirect considerations eliminated the possibility the CAMP levels had changed.65 Additionally, it was found that dexamethasone failed to inhibit histamine release from human leukocytes induced by TPA, A23187 or F - m e t - l e u - ~ h e or ~ ~ from purified human lung mast cells challenged with anti-IgE.66 Budesonide inhibited antigen-induced bronchoconstriction in actively sensitized guinea pigs immunized to produce both IgE and IgG antibodies but failed to affect bronchoconstriction in animals that only produced IgG antibodies,67 Following overnight preincubation, betamethasone inhibited release of SRS from passively sensitized human lung but did not affect histamine release.68 In two clinical ~ t u d i e s ~ ~ ' ~ ' dealing with hayfever and chronic asthma, budesonide was found to be
66
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superior to beclomethasone and produced no observable side effects. In a separate study, beclomethasone propionate aerosol produced marked improvement in patients with chronic allergic asthma.7 1 Inhaled flunisolide significantly controlled symptoms in patients with perennial rhinitis with no adverse steroidal effects.72 In a six-month study in patients with chronic airflow o b s t r u c t i o n , p r e d n i s o l o n e failed to show improvement.73
-
Miscellaneous The imidazole 29 (SQ 80,338) and the prostaglandin analog 30 (SQ 24775), both inhibited arachidonate-induced bronchoconstriction in the guinea pig but failed to alter histamine or antigeninduced bronchoconstriction. SQ 80.338 inhibited release of TXA2 from
isolated guinea pig lung.74 Astemizole, a histamine HI-antagonist with high affinity and long duration, was effective for allergic rhinitis with no sedative or cholinergic side effect^.'^'^^ Clinical studies of terfenadine (RMI 9918) have shown it to be an effective anti-HI antihistamine with no anticholinergic, CNS or CV side effect^.^^-'^ In guinea pigs and monkeys terfenadine produced no adrenergic or histamine H2-antagonism. Amrinone, a cardiotonic compound, has been shown to inhibit bronchoconstriction in dogs and tracheal contractions in guinea pigs induced by histamine." The xanthine, enprofylline
(z), showed bronchodilator activity 5 Lack of CNS ef-
x theophylline with no emetic, CNS or renal effects.
fects in asthmatic patients were reportedly due to absence of a 1nitrogen substituent.82 BB1502 (32) was reported to be a bronchodilator with long duration in allergic asthma in guinea pigs when administered prior to allergic challenge.83 The pyrimidobenzothiazole 2 and its 8-chloro analog 34 inhibited allergic bronchospasm in rats with E D ~ ~ s of 0.38 and 0.11 mg/kg, r e ~ p e c t i v e l y . ~Inhaled ~ thiazinamium chloride
Pr
0 I
32 -
showed potent bronchodilator activity with rapid onset and moderate duration and no motor or CV effects in guinea pigs and monkeys.85 Inhaled ipratropium bromide, an anticholinergic agent, was found to be a clinically effective bronchodilator with a low incidence of side effects.86-89 The pyrazolo-pyrimidine 35 and the pyrazolotriazine 6 were PDE inhibitors with potencies 15x and 67x theophylline respectively. 36 was selective for lung PDE over heart PDE and protected against histamine-induced bronchospasm in guinea pigs. y 9 1
Chap. 7
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R
k N w36
R :NHPr, R'-Br,
R2Z
-- N
References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12 13 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37 38. 39
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Is,
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40. M. Agata, H. Goto, Y. Tsuriya, K. Tachibana and T. Kuroda, Japan. J. Pharmacol., 32, 689 (1982). 41. K. Goto, M. Hisadome and M. Terasawa, Int. Archs. Allergy Appl. Immunol., @, 332 (1982). 42. A. R. Gellert, R. M. Rudd, P. R. Studdy, D . M. Geddes and B. R . Boeree, Br. J. Clin. Pharmacol., 14,608P (1982). 28 (1982). 43. W. A. Taylor and M. D. Hammond, Allergy, E, 44. H. S . Nelson, Chest, 82, 3355 (1982). 45. P. Andersson, 0. A. T. Olsson and B. Waldeck, Acta. Pharmacol. et. Toxicol., 358 (1982). 46. C . 4 . Lofdahl, Eur. J. Respir. Dis., 63, Supp 120 (1982). 47. C.4. Lofdahl, B. Bengtsson, K. Svedmyd and N. Svedmyd, Allergy, 37, 351 (1982). 48. M. L. Cohen, K. S. Wiley and K. G . Bemis, Naunyn-Schmiedeberg's Arch. Pharmacol., 320, 145 (1982). 49. C. L. Zanetti, H. D. Rotman and A. J. Dresner, J. Clin. Pharmacol., 22, 250 (1982). 50. R . A. Nichlas, V. E. Whitehurst and R. F. Donohue, New Eng. J. Med., 307, (1982). 51. C. L. Armour, I. J. Nicholls and R. R . Schellenberg, J. Allergy Clin. Immunol., 69, 108 (1982). 52. K. Svedmyr, Allergy, 2 , 119 (1982). 53. R . K. Elwood and R. J. Abboud, J . Allergy Clin. Immunol., 69, 467 (1982). 54. B. Hegardt, 0 . Lowhagen, N. Svedmyr and G . Granerus, Allergy, 21, 407 (1982). 55. L.-A. Svensson and T. Olsson, North American Medicinal Chemistry Symposium, Abstract 36, p. 80, Toronto, Canada, June, 1982. 56. K. Yamada, M. Takeda, N. Itok, N. Umino, K. Ikezawa, A. Kiyomoto, K. Aoe, K. Kotera and T. Iwakuma, Chem. Pharm. Bull., 30, 1588 (1982). 57. A. Mukhopadhyay, D. J. Sobev, J. Chang, R. T. Slenn, H. M. Amin, D. D. Miller and D. R. Feller, Eur. J. Pharmacol., E,209 (1982). 58. N. Decker, M. C. Quennedey, B. Rouot, J. Schwartz and 3. Velly, J. Pharm. Pharmacol., 34, 107 (1982). R. Patel and J. W. Kerr, Clin. Allergy, 125, 15 (1982). 59. 60. C. H. Fanta, C. S . Venugopalan, P. G . Lacouture, and J. M. Drazen, Am. Rev. Resp. Dis., 125,61 (1982). 61. P. E. Malo, M. A. Wasserman, and R. L . Griffen, J. Pharmacol. Exp. Ther., 3,410 (1982). 62. T. Suzuki, K. Mori and M. Uchidu, Eur. J. Pharmacol., 85, 155 (1982). 63. E. B. Weiss, J. Mackowicz and L. Barbero, Allergy, 2 1 , 7 1 3 (1982). 64. R. G. Townley, Chest, 82, 401 (1982). 65. R . P. Schleimer, D. W. MacGloshen, Jr., E. Gillespie and L. M. Lichtenstein, J. Immunol., 2 ,1632 (1982). 66. R. P. Schleimer, M. A. Wasserman, D. W. MacGlashan, Jr., S . P. Peters, G . K. Adams, L . M. Lichtenstein and N. F. Adkinson, Jr., J. Immunol., in press. 67. P. Andersson and R. Brattsand, Br. J . Pharmacol., 76, 139 (1982). 68. C. V. Hammond, M. D. Hammond and W. A. Taylor, Int. Archs. Allergy Appl. Immunol., 67, 284 (1982). 69. Pipkorn and H. Rundcrantz, Acta. Otolaryngol., 274 (1982). 70. R . F. Wiley, D. J. Godden, J. Carmichael, P. Preston, M. H. France and G . K. Crompton, Eur. J. Resp., 9, 138 (1982). 71. V. A . Malfitan, Clin. Ther., 4 , 472 (1982). 72. P. C. Turkeltaub, P. S. Norman, J. D. Johnson and S . Crepes, Allergy, 37, 303 (1982). 73. T. C. Stokes, J. F. O'Reilly, J. M. Shaylor and B. D . W. Harrison, The Lancet, p. 345, August 14, 1981. 74. R. Greenberg, M. J. Antonaccio and T. Steinbacher, Eur. J. Pharmacol., 80, 19 (1982). 75. R. Brobyn, M. Benoil and N. Madin, J. Allergy Clin. Immunol., 69, 110 (1982). 76. J. R. Caldwell, J. Allergy Clin. Immunol., 69, 154 (1982). 77. A. N. Nicholson, Arzneim. Forsch., 32(II), 1191 (1982). 78. H. Gastpar and H. A. Dieterich, Arzneim. Forsch., 32(II), 1209 (1982). 79. M. L. Brandon and M. Weiner, Arzneim. Forsch., 32(II), 1204 (1982). 80. H. C. Cheng and J. K. Woodward, Drug Dev. Res., 2 , 181 (1982). 81. Z. E. Mielens and D . C. Buck, Pharmacol., 25, 262 (1982). 82. G. Kjellin and C. G. A. Persson, North American Medicinal Chemistry Symposium, Abstract 49, p. 93, Toronto, Canada, June, 1982. 83. H. Kamei, M. Hirano, K. Kawano, H. Imanishi and H. Kawaguchi, Japan. J. Pharmacol., 3,315 (1982). 84. J. P. Yevich, D. 1. Temple, Jr., R. R. Covington, D. A. Owens, R. J. Seidehamel and K. W. Dungan, J. Med. Chem., 25, 864 (1982). 85. A. 3. Lewis, A. Dervinis and M. E. Rosenthale, Eur. J. Pharmacol., 80, 171 (1982). 86. S . M. Tarlo, I. Broder and P. Corey, Curr. Ther. Res., 32, 265 (1982). 87. D . W. Crockroft, D. J. Cotton and B. A . Berscheid, Curr. Ther. Res., 32, 138 (1982). 88. A. S. Rebuck, K. R . Chapman and A. C. Brande, Chest, g , 5 5 s (1982). 89. W. M. Tullet, K. R. Patel, K. E. Berkin and J. W. Kerr, Thorax, 21, 737 (1982). 90. K. Senga, D. E. O'Brien, M. B. Scholten, T. Novinson, J. P. Miller and R . K. Robins, J. Med. Chem., 9, 243 (1982). 91. R. H. Springer, M. B. Scholten, D . E. O'Brien. T. Novinson. J. P. Miller and R. K. Robins, J. Med. Chem., 25, 235 (1982).
z,
e,
-
Pharinacodynamic A g e n t s
W i l l i a m T . Comer, B r i s t o l - M y e r s R e s e a r c h a nd D e ve lopm e nt 345 P a r k Avenue, N e w York, New York 10154 Chapter 7 .
Pulmonary and A n t i a l l e r g y A ge nts
J o h n D . C a t t an d E l i z a b e t h G i l l e s p i e , B r i s t o l - M y e r s P r e c l i n i c a l C a r d i o v a s c u l a r R e s e a r c h , E v a n s v i l l e , I n d i a n a 47721 I n t r o d u c t i o n - Compounds o f s p e c i f i c i n t e r e s t w i t h r e s p e c t t o a l l e r g y and a s t h m a a r e d i s c u s s e d i n some o f t h e f o l l o w i n g s e c t i o n s . R e s e a r c h on a r a c h i d o n i c a c i d and i t s v a r i o u s m e t a b o l i t e s proceeded a t a b r i s k pace i n 1 9 8 2 . S e v e r a l g e n e r a l reviews d e a l i n g w i t h c y c l o o x y g e n a s e a n d / o r l i p o x y genase p r o d u c t s have appeared.'-5 However, u n t i l c l i n i c a l d a t a a p p e a r on agents a f f e c t i n g arachidonic a c i d m e t a b o l i t e s , whether i n i n h i b i t i n g s y n t h e s i s o f l e u k o t r i e n e s , b l o c k i n g r e l e a s e o r e f f e c t s o f SRS, o r i n h i b i t i n g lipoxygenase products, t h e c l i n i c a l b e n e f i t of t h i s type of agent remains u n c l e a r . Slow R e a c t i n g S u b s t a n c e (SRS) an d L e i i k o t r i e n e s (LTs) - S e v e r a l s i g n i f i c a n t p a p e r s h a v e a p p e a r e d wh i ch d e s c r i b e new s y n t h e t i c p r e p a r a t i o n s o f leukotrienes. A s t e r e o s p e c i f i c s y n t h e s i s of l e u k o t r i e n e s from 2-deoxyD - r i b o s e h a s b e e n d e s c r i b e d , 6 and LTC4, LTD4, a n d LTE4 h a v e b e e n p r e p a r e d from 5-HPETE by a s t e r e o s e l e c t i v e , b i o m i m e t i c r o u t e . Eight synthetic i s o m e r s o f LTD4 h a v e b e e n s y n t h e s i z e d a nd compared. Only t h e 5 S , 6 R , 7 , 9 trans,ll,l4-cis i s o m e r was i d e n t i c a l t o b i o l o g i c a l l y - g e n e r a t e d g u i n e a p i g LTD4 i n a l l r e s p e c t s . ' I n a n o t h e r s t u d y i n v o l v i n g a n a l o g s o f LTC4 and LTD,, i t was f o u n d t h a t t h e 5-OH and c a r b o x y l g r o u p s were e s s e n t i a l f o r SRS a c t i v i t y b u t v a r i a t i o n o f t h e p e p t i d e m o i e t y o n l y p a r t i a l l y decreased a ~ t i v i t y . S ~ u l f o n e s o f L I T 4 , LTD4 and LTE4 h a v e b e e n p r e p a r e d from t h e c o r r e s p o n d i n g LTs. l o They were b i o l o g i c a l l y s i m i l a r t o t h e LTs with about half t h e potency. l1 Ll'C4 a d m i n i s t e r e d by a e r o s o l was shown t o c a u s e b r o n c h o c o n s t r i c t i o n i n n o r m a l human v o l u n t e e r s > 2 w h i l e i n c u l t u r e s o f human l u n g c e l l s b o t h LTC, a n d LTD413 were f o u n d t o i n c r e a s e mucus p r o d u c t i o n . I n monk e y s , LTC4 c a u s e d a d e c r e a s e i n p u l m o n a r y c o m p l i a n c e , c o n t r a c t e d i s o l a t e d t r a c h e a l s p i r a l s and r e d u c e d c i r c u l a t i n g l e u k o c y t e s . l 4 S t u d i e s i n g u i n e a p i g s h a v e a t t e m p t e d t o e l u c i d a t e t h e mechanisms o f a c t i o n s of t h e LTs. In g u i n e a p i g t r a c h e a l p r e p a r a t i o n s , LTC4 c a u s e d a d e c r e a s e i n CAMP b u t d i d n o t a l t e r cGMP. The c o n t r a c t i o n s c a u s e d b y LTC4 i n t h i s s t u d y were n o t a l t e r e d by i n d o m e t h a c i n . l 5 I n a n o t h e r s t u d y , LTC4 and LTD4 were shown t o r e l e a s e TXA2 and p r o s t a g l a n d i n - l i k e m a t e r i a l from g u i n e a p i g l u n g a nd induce c o n t r a c t i o n i n parenchymal s t r i p s . Both t h e s e a c t i o n s were i n h i b i t e d by i m i d a z o l e , a t h r o mb o x an e s y n t h e t a s e i n h i b i t o r . l 6
SRS A n t a g o n i s t s - S e v e r a l compounds o t h e r t h a n FPL 55712 a n d i t s a n a l o g s The bromo d e r i v a t i v e 1 s e l e c t i v e l y a n t a g o n i z e t h e a c t i o n s o f SRS. inhibited the SRS-induced contractions of guinea pig ile um " (ICs,-, = 5 0 PM)~; w h i l e t h e f u s e d r i n g a n a l o g 2 i n h i b i t e d w i t h a n BL5255 ( 3 ) a n t a g o n i z e d SRS and LTD4-induced c o n t r a c t i o n IC5o o f 5 pM.
ANNUAL REPORTS I N MEDICINAL C H F N I S T R Y 4 I I
Copyright D 1983 by Academ~cPress. Ine All righis of reproductiontn any form r e w v e d . ISBN 0- I20405 I 8 4
Sect. I1
62 -
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Pharmacodynamic Agents
Comer, Ed.
of guinea pig tracheal rings over the concentration range 10-6-10-4M.l9 At the higher concentrations, histamine- and methacholine-induced contractions were also inhibited. The propenamides k and 5 are representative of a series that was shown to antagonize SRS actions on guinea pig ileum at 1 0 - ~ ~ . 2 O ' ~ 1
coo"
4
A =SJHCOCH=CHCOOH
5
A
z
OH
6
R e H
7 R=Me r;r Leukotriene Synthesis Inhibitors - The pyrrole prostacyclin analog U-60,257 (6) and its methyl ester U-56,467 (1)inhibited LTC4 and LTD4 synthesis induced by calcium ionophore in human polymorphonuclear leukocytes.22 U-60,257 did not inhibit formation of 12-HETE in human platelets but did inhibit antigen-induced bronchopulmonary changes in monkey and guinea pig in v ~ v o .Ro~ 21-7634 ~ ( S ) inhibited the synthesis 0-
0
8 -
9 -
of SRS in rat peritoneal mast cells and TXA2 synthesis in perfused guinea pig lung at similar concentrations but did not inhibit TXA2 production induced by direct perfusion of SRS into the lung.24 A preliminary report indicated that the urea 9 is a selective inhibitor of LTCd synthesis.25 Diethylcarbamazine inhibited LTB4 and C4 biosynthesis in calcium ionophore stimulated mouse mastocytoma cells, while cyclooxygenase and lipoxygenase activity were unaffected.26 Lipoxygenase Inhibitors - The non-steroidal anti-inflammatory agent benoxaprofen, previously reported to selectively inhibit lipoxygenase at therapeutic levels, failed to be efficacious in aspirin-sensitive patient^.^' In in vitro studies, benoxaprofen inhibited SRS release from human and guinea pig lung following antigen challenge and reduced SRS release in vivo but did not antagonize the actions of SRS.28 Nafazatrom (Bay g 6575) inhibited tumor cell lipoxygenase activity but not cyclooxygenase product formation at pM concentrations.29 The 5,6-methanoleukotriene A4, (KCN-TEI-6173, E),a stable LT, inhibited 5-lipoxygen-
Chap. 7
Pulmonary and Antiallergy
Catt, Gillespie
63
ase synthesis, (IDSo = 18 pM) and did not inhibit prostaglandin (cyclooxygenase) synthesis at concentrations up to 150 The acetylenic
CH J,COOH
CSHll
5,6-dehydroarachidonic acid, 11, inhibited 5-lipoxygenase in RBL extracts (K = 15 pM) but was much less active in intact cells due to metabolism. The flavonoid baicalein. l2, selectively inhibited platelet lipoxygenase (IC50 = 0.12 VM).~* '
12 -
Mediator Release Inhibitors - The imidazopyridine, 3-deaza-SIBA (E),at concentrations of approximately 10-4M, inhibited IgE-mediated histamine release from rat basophilic leukemia cells and histamine release from rat peritoneal mast cells induced by compound 48/80, calcium ionophore, and ATP.33
hie
14 R = CH,CH,OH 1 5 R-H -
16 -
In asthmatic patients, tiaramide improved lung function and reduced the need for inhaled beta agonist.34 Tiaramide (2,RHC 2592-A) and its major metabolite, desethanol tiaramide (2,RHC 3281) inhibited IgE- and IgG-mediated histamine release from rat peritoneal mast cells and guinea pig lung slices, respectively. 3 5 In other studies, tiaramide inhibited formation of TXA2 and antagonized bronchoconstrictor mediators with selectivity for PGF2a and SRS in guinea pigs. The hydrazine derivative 16 had activity 3 x DSCG in the rat PCA test and also inhibited histamine release from rat mast The pyrimidine urea 17 inhibited IgE-mediated histamine release from human basophils, as well as the PCA in rats.39 The oxamate 18 (MTB) inhibited IgE-mediated histamine release from rat peritoneal cells and the PCA reaction in rats and guinea pigs.4o The orally active antiallergy compound traxanox sodium inhibited histamine release from rat mast cells induced by antigen or compound 48/80 but had only marginal effects on calcium ionophore-induced release. The azaxanthine 19 - (M&B 22,948) was 30 x DSCG as a mediator release inhibitor and was
*'
64 -
Sect. I1
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Pharmacodynamic Agents
Comer, Ed.
effective against exercise-induced but not histamine-induced bronchoconstriction (fall in FEV,) in asthmatic patients.42 TR 2855, a chromone that inhibits antigen-induced release of histamine and SRS from passively sensitized human lung, relaxed human bronchial and guinea pig tracheal muscle and caused bronchodilation in guinea pigs. 43 p-Adrenoceptor Agonists - Clinical trials in asthmatic patients of the p2-agonists terbutaline, albuterol, fenoterol and carbuterol failed to differentiate between the group in that all four compounds showed the side effects of tremor and t a c h y ~ a r d i a . ~ ~ Another ' ~ ~ study with two new highly selective p2-agonists D-2343 (20) and QH25 (21) also failed to separate bronchodilator and tremorigenic effects and concluded that the p2-adrenoceptor in bronchial muscle and skeletal muscle are the same.46 D-2343 and QH25 were found to have a potency of 0.2 x terbutaline and 12 x albuterol, respectively.47 Although clenbuterol showed a selectivity for p2-adrenoceptorsY its high agonist potency was attributed to high affinity for the fi-adrenoceptor rather than efficient adrenoceptor activation.48 In patients with reversible airway obstruction, procaterol exhibited a dramatic bronchodilator effect with duration up to 12 h.49 An FDA study commission has concluded from recent animal studies that cardiac toxicity of p-adrenoceptor agonists was enhanced by concomitant administration of methyl xanthines There are , however , conflicting reports; in a study of albuterol and theophylline in ~ o m b i n a t i o n and ~ ~ a second study of theophylline and terbutaline results indicated that low-dose bronchodilator/theophylline combinations gave better bronchodilation with fewer tremors and tachycardia than a high dose of either drug alone.52 In a different context the combination of fenoterol and ipratropium, an anticholinergic bronchodilator (see below), achieved bronchodilatory efficacy similar to high doses of fenoterol alone but with fewer side effects.13
.
The activity of the terbutaline analog KWD 2131 (22) in bronchial allergen challenge was shown to be due entirely to bronchodilation with 20 -
B
C
R
H
OH
H
CHfQ
I-\
H
22 23 -
-
A
OMe H
OH
H
OH
OH
OCONMe,
H
OCONMeo
H
Chap. 7
Pulmonary and Antiallergy
Catt, Gillespie
2
no antiallergic effect being observed.'* The terbutaline pro-drugs KWD 2183 (g) and D 2438 (2)were potent bronchodilators in guinea pigs and maintained therapeutic plasma levels in dogs for 23 h and 12 h respectively. These compounds caused a significantly smaller increase in heart rate than did terbutaline.55 The bronchodilatory activity of 26 was found to be in the 2-isomer as was the case for its parent TMQ (g).56 The g-methyl derivatives, 27 and 2 8 , were 15- and 4-times more selective for p2-adrenoceptors over E-adrenoceptors than TMQ. 57
!L!il%h
bMe
25
OH
H
H
H
26
H
OH
H
H
27
OH
H
Me
H
threo
28
OH
H
H
Me
erythro
A study of the four drugs isoprenaline, terbutaline, albuterol, and soterenol as to the effect of N-aralkyl substitution indicated that this substitution increased 8 2 - and al-adrenoceptor selectivity with the 8 2 effect most noticeable with soterenol.5s
Calcium-Antagonist - Verapamil and nifedipine were found to inhibit exercise- induced b ronchoconstric tion in asthmatic subjectsP9 while in animal studies nifedipine was found to inhibit bronchoconstriction induced by histamine in both guinea pigs60 and dogs.61 In an in vitro study, methoxyverapamil (D-600) inhibited concanavalin A-induced histamine release and calcium ion influx in rat peritoneal mast cells but did not inhibit compound 48/80-induced histamine release.62 Verapamil inhibited experimental anaphylaxis in guinea pig tracheal smooth muscle but failed to inhibit histamine release from tracheal mast cells.63 Nifedipine inhibited the PCA reaction in rats with a potency 50 x DSCG but did not inhibit skin reactions induced by histamine or methacholine. Corticosteroids - The mechanism whereby anti-inflammatory steroids inhibit IgE-mediated histamine release from human leukocytes was explored. It was shown that overnight culture of cells with dexamethasone did not alter either total or occupied Fc receptor number and indirect considerations eliminated the possibility the CAMP levels had changed.65 Additionally, it was found that dexamethasone failed to inhibit histamine release from human leukocytes induced by TPA, A23187 or F - m e t - l e u - ~ h e or ~ ~ from purified human lung mast cells challenged with anti-IgE.66 Budesonide inhibited antigen-induced bronchoconstriction in actively sensitized guinea pigs immunized to produce both IgE and IgG antibodies but failed to affect bronchoconstriction in animals that only produced IgG antibodies,67 Following overnight preincubation, betamethasone inhibited release of SRS from passively sensitized human lung but did not affect histamine release.68 In two clinical ~ t u d i e s ~ ~ ' ~ ' dealing with hayfever and chronic asthma, budesonide was found to be
66
Sect. I1
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Pharmacodynamic Agents
Comer, Ed.
superior to beclomethasone and produced no observable side effects. In a separate study, beclomethasone propionate aerosol produced marked improvement in patients with chronic allergic asthma.7 1 Inhaled flunisolide significantly controlled symptoms in patients with perennial rhinitis with no adverse steroidal effects.72 In a six-month study in patients with chronic airflow o b s t r u c t i o n , p r e d n i s o l o n e failed to show improvement.73
-
Miscellaneous The imidazole 29 (SQ 80,338) and the prostaglandin analog 30 (SQ 24775), both inhibited arachidonate-induced bronchoconstriction in the guinea pig but failed to alter histamine or antigeninduced bronchoconstriction. SQ 80.338 inhibited release of TXA2 from
isolated guinea pig lung.74 Astemizole, a histamine HI-antagonist with high affinity and long duration, was effective for allergic rhinitis with no sedative or cholinergic side effect^.'^'^^ Clinical studies of terfenadine (RMI 9918) have shown it to be an effective anti-HI antihistamine with no anticholinergic, CNS or CV side effect^.^^-'^ In guinea pigs and monkeys terfenadine produced no adrenergic or histamine H2-antagonism. Amrinone, a cardiotonic compound, has been shown to inhibit bronchoconstriction in dogs and tracheal contractions in guinea pigs induced by histamine." The xanthine, enprofylline
(z), showed bronchodilator activity 5 Lack of CNS ef-
x theophylline with no emetic, CNS or renal effects.
fects in asthmatic patients were reportedly due to absence of a 1nitrogen substituent.82 BB1502 (32) was reported to be a bronchodilator with long duration in allergic asthma in guinea pigs when administered prior to allergic challenge.83 The pyrimidobenzothiazole 2 and its 8-chloro analog 34 inhibited allergic bronchospasm in rats with E D ~ ~ s of 0.38 and 0.11 mg/kg, r e ~ p e c t i v e l y . ~Inhaled ~ thiazinamium chloride
Pr
0 I
32 -
showed potent bronchodilator activity with rapid onset and moderate duration and no motor or CV effects in guinea pigs and monkeys.85 Inhaled ipratropium bromide, an anticholinergic agent, was found to be a clinically effective bronchodilator with a low incidence of side effects.86-89 The pyrazolo-pyrimidine 35 and the pyrazolotriazine 6 were PDE inhibitors with potencies 15x and 67x theophylline respectively. 36 was selective for lung PDE over heart PDE and protected against histamine-induced bronchospasm in guinea pigs. y 9 1
Chap. 7
Pulmonary and Antiallergy
Catt, Gillespie
67
R
k N w36
R :NHPr, R'-Br,
R2Z
-- N
References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12 13 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37 38. 39
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