Chapter 8. Pulmonary and Antiallergy Agents

Chapter 8. Pulmonary and Antiallergy Agents Dee W. Brooks, Randy L. Bell, and George W. Carter Abbott Laboratories, Abbott Park, Illinois 60064 Introduction - The prevalence of pulmonary and allergic diseases continues to stimulate a broad range of research into new therapies for these conditions. The potential involvement of leukotrienes in the pathogenesis of asthma has focused attention on the search for agents that antagonize the actions of these potent biological substances and/or inhibit 5lipoxygenase. Several peptide leukotriene antagonists have progressed to the clinic and early results regarding their activity in preventing LTD4-induced bronchoconstriction in man and their efficacy in treating asthmatics have appeared (1,2). Platelet activating factor (PAF) has been implicated in airway hyperreactivity associated with asthma suggesting the potential utility of PAF antagonists in the rreatment of asthma (3). Other approaches being pursued to discover drugs for asthma and allergic diseases include: mediator release inhibitors, thromboxane antagonists and biosynthesis inhibitors, non-sedating Hl antihistamines and bronchodilators. Evidence that the proteolytic enzyme elastase plays a major role in lung injury in chronic pulmonary diseases such as emphysema has promoted the search for specific elastase inhibitors. LEUKOTRIENES The biological effects of leukotrienes, their potential involvement in diseases (4-7) and the discovery and evaluation of antagonists and biosynthesis inhibitors (8- 10) were actively investigated. Leukotrienes were detected in sputum of patients with chronic bronchitis (1 1) and LTC4 levels were found elevated in the blood of children undergoing an acute asthmatic attack (12). A direct effect on airway smooth muscle was suggested for LTD4-induced bronchoconstriction in man (13). Activation of the LTD4 receptor on RBL1 cells was shown to induce phosphatidyl inositol hydrolysis which was G-protein regulated (14). The successful cloning of 5-lipoxygenase and LTA4-hydrolase, two key enzymes in the biosynthetic pathway leading to the leukomenes, has been reported (15-17). An interesting mechanism for regulating leukotriene production was suggested for sodium diclofenac. In addition to being a potent cyclooxygenase inhibitor, it enhanced the spontaneous uptake of arachidonic acid into the cellular triacylglycerol pool thereby reducing the availability of arachidonic acid for metabolism to leukomenes (18). Leukotriene Antagonists - FPL-55712 (I)has been the prototype for the development of several leukomene antagonists. SC-39070 (2)displayed selective antagonism of LTD4 with a pA2 = 8.2 on guinea pig ileum. A dose of 10 mg/kg PO blocked LTD4-induced bronchoconstriction in guinea pigs for 20 hours (19). The structure-activity relationships (SAR) in the series leading to LY 17 1,883 (2) showed that the 2-propyl-3-hydroxy-4acetylphenoxy unit was important for activity and a 4-7 methylene unit spacer was optimal between the phenoxy and tetrazole units (20,21). A single 400 mg dose of 3 in normal subjects caused a rightward shift in the LTD4 dose response curve for FEVI, 4.6-fold and for Vmaxgo, 6.3-fold (1). In the first long term study of a LT antagonist in asthmatic patients, 2, given 400 mg twice a day reduced symptom scores, decreased the use of p2 agonist and increased FEVl (2, 22). The SAR leading to LY 163,443 (4) was reported was described (24). (23) and a series leading to Ro23-3544 ANNUAL REPORTS IN MEDICINAL CHEMISTRY -23

69 -

Copyright iE 198X hy Academic Press. Inc All right\ o f reproduction in any form r r w v e d

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Using a hyperreactive rat model, two LTD4 antagonists, L-647,438 (6) and L649,923 (2) were evaluated after oral administration and found to inhibit antigen-induced dyspnea with ED50 values of 5.75 and 1.3 mg/kg, respectively (25). A longer duration of action was observed for (>6 hrs) compared to 6 (<4 hrs). In man, a 3.8-fold shift in the airway dose-response curve to inhaled LTD4 was observed 1 h after ingestion of a 1 g dose of 2 , whereas no effect on histamine-induced bronchoconstriction occurred (26). In mild asthmatics with known early and late responses to antigen challenge, the same dose produced only a small protective effect against the early phase response and no effect on the late response (27). L-649,923 (2) was poorly tolerated and adverse effects included abdominal discomfort and diarrhea. The aerosol administered LT antagonist, L-648,051 a),was evaluated in a trial with nine normal subjects and only partially inhibited LTD4induced bronchoconstriction (2).

z

The potent and selective LT antagonist ICI-198,615 (2)demonstrated competitive antagonism of LTD4 and LTE4 contractile effects on guinea pig trachea and parenchymal lung strips with pA2 values of 10.1 to 9.5 (28) and inhibited 3[Hl-LTD4 binding to guinea pig lung receptors with a Ki of 0.27 nM (29). Against LTD4 induced dyspnea in the guinea pig, 2 was effective by iv, PO,or aerosol administration and the pharmacological half-life of the compound after oral administration was in excess of 16 hrs (30). Further development of this series provided an even more potent analog lQ (31). SKF-104353 (La)with stereochemistry similar to LTD4, had a Ki of 5 nM whereas the enantiomer SKF-104373, was about 35-fold less potent (32). Further characterization showed that J.l inhibited LTD4 binding to human lung membranes with a Ki of 10 nM. It antagonized LTD4-induced contraction of guinea pig trachea with a pA2 of 8.6 but was without effect on LTC4 elicited contractions. On isolated human bronchial tissue, the compound antagonized contractions induced by LTD4 with pA2=8.2 and LTC4 with pKb=8.3. Aerosol administered compound inhibited LTD4-induced bronchoconstriction in anesthetized guinea pigs. Additional pharmacology of U h a s been reported (33). By combining structural features of 1-alkylimidazoles,known thromboxane synthase inhibitors and pyrido[2,1-b]quinazoline amides with activity as LT antagonists, a series of compounds with dual activity was developed (34). Compound 12 inhibited SRS-Ainduced contraction of guinea pig ileum (Ic50=1.0 pM) and inhibited TXA2 synthase (IC50=0.2 pM). It was orally active in reducing bronchoconstriction induced by antigen

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(ID50=50 mg/kg), PAF (ID50=13 mgkg) and histamine (ID50=39 mg/kg). This compound was also active in the rat PCA model but was less potent than the parent carboxylic acid U. Compounds have been discovered which inhibit leukotriene production and antagonize their actions. The SAR leading to REV-5901 0was reported (35). It inhibited 5-LO in rat neutrophils with IC50 of 0.12 pM and blocked LTC4-induced contraction of guinea pig lung parenchyma with IC50 of 3.6 pM. At 10 mgkg id, 14 inhibited antigen-induced bronchoconsmction in actively immunized guinea pigs. This compound also inhibited leukotriene release from human lung tissue at 1-10 pM and antigen-induced histamine release at 10 pM (36). In man, provided no protection against histamine- or LTD4-induced bronchoconstriction (2). Compound fi,a 5-LO inhibitor and LTD4 antagonist was developed from a previous inhibited 5-LO with ICso's of 2.4 series (37). Two phenylephrine derivatives 14 and U, and 19.6 pM and LTD4-induced bronchoconstriction in guinea pig with EDSO'S of 56 and 36 mgkg po (38). Against LTD4-induced bronchoconstriction in guinea pigs, WY-48252 us> had an ED50 of 0.1 m a g by intragasmc administration and a pharmacological halflife of 5 hrs (39). This compound antagonized LTD4-induced contraction of guinea pig trachea with a pKb of 7.6 and also inhibited 5-LO and cyclooxygenase in rat neutrophils with an IC50 of 4.6 pM and 3.3 pM, respectively.

I

12 U

IC! Ri=CH3,

-

X- HN-(CH2)4

X=CH2

1 4 X=CHOH(CH2)&H3

X=OH

Inhibitors of Leukotriene Biosvnthesis - A mechanism for the reaction catalyzed by soybean lipoxygenase has been proposed involving concerted deprotonation and electrophilic addition of Fe(1II) to carbon, resulting in an organouon intermediate that reacts by oxygen insertion (40). A chemical model for this process has been demonstrated by the oxygen insertion reaction of allylic tin compounds in the presence of FeBr3 at low temperature (41).

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L-65 1,392 U p ) blocked LTB4 formation in ionophore-challenged rat polymorphonuclear leukocytes with an IC50 of 60 nM (42). It inhibited antigen-induced dyspnea in a hyperreactive rat model with ED50 of 0.8 mgkg PO (29) and at 5 m@g PO inhibited early and late pulmonary responses to allergen-induced bronchoconstriction in squirrel monkeys (43). A series of arylalkyl- and arylalkenyl hydroxamic acids was found to be potent in vitro inhibitors of 5-LO (44). For example, the biphenylpropenyl hydroxamate ZQ inhibited RBL-1 supernatant 5-LO with IC50 of 22 nM. The hydroxamic acid 2L was shown to inhibit leukotriene biosynthesis in vivo in a rat peritoneal anaphylaxis model when administered ip, ED50 = 0.2 m a g ; however, it provided only 66% inhibition at 100 m a g PO (45). Pharmacokinetic evaluation of 21 demonstrated that it was rapidly metabolized to the corresponding inactive carboxylate (iv T1/2 c5 min). Structural modifications were examined and 2-arylpropionyl hydroxamates were found to be less prone to this metabolism (45). Moving the alkylaryl group to the nitrogen provided a series of hydroxamates with improved oral activity, as demonstrated for A-63162 (22) with an ED50 of 8 mgkg PO in a rat anaphylaxis model (46). From another series of hydroxamate inhibited LTB4 synthesis in human PMNL with an IC50 of 0.1 compounds, BW-A4C pM; in the rat, 50 mgkg PO provided prolonged inhibition of ionophore-stimulated LTB4 production in an ex vivo whole blood assay (47,48). BW A4C also blocked antigeninduced bronchospasm in anesthetized guinea pigs.

(u)

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S-26431 (24)was reported to be an orally effective 5-LO inhibitor (49). From a series of 1H-benzimidazol-4-01~,compound inhibited 5-LO with an IC50 of 3.4 pM and significantly inhibited the release of SRS-A in a rat passive peritoneal model of anaphylaxis at 200 pM ip (50). Nafazatrom given orally (2 x 3 g) was ineffective against antigen-induced bronchoconstriction in man (51). This result was rationalized by the fact that plasma concentrations of drug were too low for effective leukouiene biosynthesis inhibition.

PLATELET ACTIVATING FACTOR (PAR Reviews have appeared summarizing the potential pathophysiological role of PAF (3,5233) and the properties of PAF antagonists (54). PAF was reported to potentiate the contraction caused by LTD4 in guinea pig trachea (55). Studies using guinea pig trachea, bronchus, and parenchyma indicated that PAF is not a direct agonist of bronchoconsmction (56). Several compounds from different drug classes afforded protection in PAF-induced

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lethality in mice, suggesting that leukomenes are not the sole mediators of PAF effects (57). PAF induced neutrophil aggregation occurs by two mechanisms: one dependent on and one independent of LTB4 (58). A screening technique for PAF antagonists using neutrophil elastase release and microtiter plate technology was described (59).

u)

for PAF Antagonists - The cyclic analog 26 had similar potency as CV-3988 inhibition of PAF-induced rabbit platelet aggregation with an ICsO of 2-4 pM (60). A series of ether-chain homologs of PAF, from C1 to C20 was synthesized and their agonist activity was found to be related to the hydrophobicity of the chain with c16-c18 providing maximum activity (61). Replacement of the ether oxygen with methylene or sulfur or by an ester function dramatically decreased potency. The 2-methyl analog of lyso-PAF and 2methoxy-PAF were found to have no effect on rabbit platelets and no hypotensive effects in rats (62). 1CH2OCONHCleH37 C

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q \,y'f'18H37

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CH3-P CH,OP63(C&k+p 27 L

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Ginkgolide B (BN 52021) (29), a natural product isolated from Ginkgo biloba leaves, is an antagonist of PAF which was used to elucidate the pathophysiological role of PAF in guinea pig passive anaphylaxis models (63). An X-ray crystal analysis of the monohydrate was reported (64) and the first total synthesis accomplished (65). BN 52063, a mixture of Ginkgolides A (28), B (29), and C (30) was used in the first study demonstrating efficacy in man of a PAF antagonist against the immediate response to inhaled allergen challenge in asthmatics (66). SRI-63-441 was shown to antagonize lung responses to PAF but was inactive against antigen-induced bronchoconstriction in Rhesus monkeys (67). Pharmacological characterization of CV-6209 showed it to be more active than z,ONO-6240 c3;r),z,and the anxiolylic etizolam (68). Differences in the abilities of PAF antagonists to prevent the actions of PAF on platelet and non-platelet tissues has led to the suggestion that there is more than one type of PAF receptor (69,70). L-652,73 1 triazolam and alprazolam exhibited inhibition of PAF-induced aggregation with IC~O'Sof 0.2, 0.1, 1.5, and 6.5 pM, respectively and serotonin secretion from rabbit platelets with ICso's of 0.05, 0.15, 0.6 and 2.5 pM, respectively (70). L652,731 (34> was effective in antagonizing PAF effects in rats (71) and blocked pulmonary hypertension in sheep induced by PAF but not by complement (72).

(a)

(u,n,

U

FH20CONHC18H37

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Etizolam was found to be a potent PAF antagonist with an IC50 of 1.3 pg/ml (73). Related compounds, brotizolam and triazolam inhibited PAF-induced human platelet aggregation with IC50's of 0.54 and 7.6 pM,respectively and inhibited intrathoracic aggregation of platelets in anesthetized guinea pigs induced by iv PAF with EDSO'S= 5 and 50 m a g PO, respectively (74). Brotizolam also inhibited bronchoconstriction, systemic hypotension and the lethal effect of iv PAF in guinea pigs. Benzodiazepines lacking the triazole ring had little or no effect against PAF in v i m . WEB 2086 was reported to block the effects of PAF in guinea pig lungs but not the anaphylactic response to antigen (75). In another study, 3was shown to be more effective in blocking antigeninduced bronchoconstriction in passively sensitized guinea pigs than actively sensitized animals (76). This compound also blocked PAF-induced changes in isolated rat lung (77).

a)

The structure of FR-900452 a specific inhibitor of PAF-induced rabbit platelet aggregation with an IC50 of 0.37 pM,has been deduced by X-ray crystal analysis of the C20,21 dihydro derivative (78). A series of simplified analogs of was synthesized and Zhad an IC50 of 0.18 pM (79). Another diketopiperazine derivative had an IC50 of was reported to be a PAF antagonist 0.69 pM (80). The sesquiterpene, L-652,469 and Ca+2 blocker with a Ki 1-4 pM for both [3H]PAF and [3H]nitrendipine binding (81). It inhibited rabbit platelet aggregation and was also orally active in inhibiting PAF-induced rat paw edema and the first phase of carrageenan-induced rat paw edema. An association of PAF receptors and calcium channels was suggested by the inhibition of PAF-induced platelet activation by calcium channel blockers, diltiazem and verapamil(82).

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OCH3

MISCELLANEOUS AGENTS Inhibitors of Elastase - Inhibition of the proteolytic enzyme elastase as a biochemically based approach to develop agents to treat chronic pulmonary diseases such as emphysema has been reviewed (83-85). Biochemical efficacy of alphal-antitrypsinreplacement therapy in deficient humans was demonstrated (86). Human leukocyte elastase (HLE) has been crystallized and data concerning its tertiary structure should be forthcoming (87). The amino acid sequence of HLE is 43% homologous to porcine pancreatic elastase (88). A crystallographic study of the complex of the irreversible beta-lactam inhibitor 411 and porcine pancreatic elastase has been reported (89). Two covalent bonds between inhibitor and enzyme are formed and a mechanism for this inhibition was discussed. A kinetic study of peptidyl trifluoromethyl ketone inhibitors of HLE revealed a slow-binding inhibition

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Brooks, Bell, Carter 7J

involving reaction of a serine residue in the enzyme with the trifluoromethyl ketone to form a hemiacetal intermediate complex (90). The inhibitor Z-Lys(Z)-Val-Pro-Val-CF3 had a Ki of 0.1 nM. A study of various 2-(alky1amino)-benzoxazinones led to 41 with Ki of 0.94 nM (91). The benzoxazinone derivative 42 is a competitive, slow-binding, inhibitor of HLE with Ki of 0.5 nM (92). Evaluation of a series of 2-pyrone analogues of elasnin led to with a Ki of 4.6 pM for HLE (93).

a

Antihistamines - The role of histamine in some of the manifestations of allergic reactions is well known; however, its role in pulmonary airway disease is controversial and as yet illdefined. Terfenadine was tested in asthmatics, at 60, 120 and 180 mg and shifted the bronchoconsmctive response to histamine 14.8, 22.9, and 34-fold but had no effect on methacholine challenge (94). In a clinical study of the response of the nasal mucosa, topical administration of azatadine (44) was effective against histamine-challenge, but not cold dry air, suggesting different mechanisms of mediator release by these conditions (95). Modification of 44 led to loratidine (45) which was devoid of sedating activity and retained antihistamine activity in animal models (96,97). In man loratidine did not affect coordination, visual acuity, memory, or mood (98). The potent histamine HI receptor was reported to have activity as a leukoniene antagonist and also antagonist, azelastine inhibited ionophore-induced release of leukomenes from human PMNL (99). LY-188695 (KB-2413) was found to have potent oral activity against histamine-induced mortality in guinea pigs, EDSOof 4.4 p g k g (100). In histamine challenged guinea pigs, 42 was active as an aerosol (101) and was effective against antigen-challengein guinea pigs (102).

a

Mediator Release Inhibitors - Disodium cromoglycate (cromolyn) remains an important antiallergic agent (103). Recent investigations suggested that cromolyn acts as an anti-PAF agent (3) and/or that it inhibits activation of inflammatory cells by decreasing the formation of complement and IgG receptors and preventing oxidative burst (104). A review of the mast cell's role in bronchospasm described the case for mast cell heterogeneity and indicated that interactions of other cells with mast cells may be very important (105). Oxatomide (48) was shown to be more potent than cromolyn, ketotifen or tranilast in inhibiting the release of PGD2 or LTC4 from guinea pig lung fragments and rat peritoneal cells stimulated with ionophore or antigen (106). The 1-(2-pyridinyl)-piperazine showed activity in rat PCA, histamine-induced bronchospasm in the guinea pig and rat mesenteric mast cell degranulation induced by compound 48/80 (107).

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Bristol, Ed.

CI-922 Csa, prevented antigen-induced secretion of histamine and LT from actively sensitized human basophils and guinea pig cells and tissues with an IC50 c15 pM (108). REV 287 1 was reported as an orally effective inhibitor of mediator release with an irreversible inhibition mechanism; fl also inhibited PAF-induced histamine release (109).

(a

0

51

a)

Bronchodilators - R-836 is a relatively potent bronchodilator, active in several guinea pig models of bronchoconstriction with the potential for less side effects compared to theophyline (110). CGS 15943 is a non-xanthine adenosine antagonist having no phosphodiesterase inhibitory activity (1 11).

H

Thromboxane Antagonists and Biosvnthesis Inhibitors - Although this type of agent was initially thought to be useful for cardiovascular diseases, there is now evidence that either biosynthetic inhibitors or receptor blockers could be useful in asthma. OKY-1581 was shown to block bronchoconsuictor responses to arachidonic acid in the cat but not to PGH2 (112). OKY-046 a thromboxane synthesis inhibitor, inhibited IgE and ionophore induced histamine release (113). In a two week clinical trial in asthmatics, with a 400 mg dose of S , bronchial response to LTD4 was assessed before and after dosing. PD20 values were significantly reduced after dosing and the compound showed no direct bronchodilating effect. It was concluded that the drug can diminish bronchial hyperreactivity.

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54

The phenyldioxanealkenoic carboxylate is a specific, competitive thromboxane A2 receptor antagonist (114) and showed pA2= 6.3, 6.84, and 6.58 for antagonism of U46619 -induced contraction of isolated rabbit and rat aorta, and guinea pig trachea, inhibited bronchoconstriction induced by U46619 in respectively. At 5 mg/kg iv, anesthetized guinea pigs for over 2 hr.

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z

a,

a

x,

a,

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