- Email: [email protected]
Discovery and structure–activity relationships of urea derivatives as potent and novel CCR3 antagonists
Bioorganic & Medicinal Chemistry Letters 22 (2012) 4951–4954
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Discovery and structure–activity relationships of urea derivatives as potent and novel CCR3 antagonists Aiko Nitta a,⇑, Yosuke Iura a, Hiroki Tomioka a, Ippei Sato b, Koichiro Morihira b, Hirokazu Kubota b, Tatsuaki Morokata b, Makoto Takeuchi b, Mitsuaki Ohta b, Shin-ichi Tsukamoto b, Takayuki Imaoka a, Toshiya Takahashi a a b
Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 9 February 2012 Revised 6 June 2012 Accepted 13 June 2012 Available online 20 June 2012
The synthesis and structure–activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC50 = 190 nM) derived from initial screening hit compound 1 (IC50 = 600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC50 = 4.9 nM) as a potent CCR3 antagonist. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Allergic diseases CCR3 antagonists Urea derivatives Proline moiety
infiltration of eosinophils to inflammatory sites may have clinical potential in allergic diseases.2–11 A series of potent amide-based CCR3 antagonists possessing 6-fluoronaphthalenyl methyl moiety in our joint research project have been reported.12–14 During these studies, we also evaluated a series of urea derivatives for CCR3 inhibitory activity that display different structure–activity relationships from amides. In this Letter, we detail our efforts to discover the urea series of CCR3 antagonists. In our initial efforts to discover potential and selective CCR3 antagonists, screening of our corporate compound library yielded several hit compounds, including compound 1 as shown in Figure
The hallmark of allergic diseases such as asthma is selective accumulation of eosinophils at inflammatory sites.1 Therefore, eosinophils are thought to play an important role in the initiation and progression of these diseases. CC chemokine receptor 3 (CCR3), a member of the seven transmembrane G-protein coupled receptor (GPCR) family, is the receptor for eotaxin and appears predominantly on eosinophils. Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites and cytokines, all of which have potential to produce the clinically observed pathophysiology. A growing body of clinical studies and animal models suggest that eotaxin and CCR3 play a major role in allergic diseases and thus, a selective CCR3 antagonist that suppresses the
O
O N
N
N
N N
N N
N H
N
F 2: IC50 = 190 nM
1: IC50 = 600 nM
Figure 1. Screening hit compound 1 and modified lead compound 2.
⇑ Corresponding author. Tel.: +81 467 32 9659; fax: +81 467 32 9891. E-mail address: [email protected] (A. Nitta). 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.06.042
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A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954
1.15 Compound 1 showed unique structural features such as tricyclic imidazolo-quinazolone and diphenylmethyl piperidine moieties and moderate inhibitory activity for CCR3 (IC50 = 600 nM). To elevate CCR3 inhibitory activity and avoid synthetic difficulty and low bioavailability of 1,16 various derivatives were synthesized. As a result, tetrahydroisoquinoline urea derivative 2 (IC50 = 190 nM) was discovered as a lead compound. The inhibitory activity of 2 against other CC chemokine receptors, CCR1, CCR2 and CCR5, was also evaluated and it resulted in no effect on them at a concentration of 10 lM. Toward optimization of the new lead compound 2, we decided to modify the linker structure of 2, which showed a length suitable for CCR3 inhibitory activity but was too flexible. To design a rigid linker, the substructure of another lead compound 3 was utilized for adjusting the positions of both terminal aromatics and central tertiary amine.12 As shown in Figure 2, therefore, the diphenylmethyl propyl piperidine moiety of 2 was converted to 6-fluoronaphthyl methyl nortropane. Moreover, the tetrahydroisoquinoline was replaced with various cyclic amines in the left part. As shown in Scheme 1, the 6-fluoro-naphthyl methyl nortropane derivatives were synthesized by activation of nortropane amine 4 with 4-nitrophenyl chloroformate,13 followed by condensation with commercially available or appropriate amines that were prepared by common routes described in Scheme 2. 6-Fluoro-1,2,3,4-tetrahydroisoquinoline, a starting material for synthesis of 5 was prepared as reported.17 The CCR3 inhibitory activity data for selected compounds are listed in Table 1. Compound 5 (IC50 = 780 nM) possessing the substructure of 2 was not effective with one-quarter of the potency of 2. As it seemed that the left aromatic ring of compounds 6 (IC50 = 59 nM) and 8 (IC50 = 52 nM) was located as the same
suitable positions of right and left aromatics
suitable length but flexible linker O
fluorine atom N
N H
F
N 2
tertiary amine
O N H
N F
rigid linker 3: IC50 = 20 nM
O N
N H
N F
Figure 2. Important pharmacophores for CCR3 inhibitory activity and new compound design. O H2N
a, b N
4
R
N H
N
F
F
5-29
Scheme 1. Reagents and conditions: (a) ClCO2p-NO2Ph, NaHCO3, CHCl3; (b) amine, Et3N, CHCl3.
NBn
O
F
NBn
a
O2N
F F
NO2
30
b, c HN
N H
F
NO2
b, c
N H
33
CbzHN O N
f
38
NFmoc
41
HN
Cl
N
g
N
R Cl
39a: R=4-F 39b: R=4-NH2 39c: R=2,6-diCl 39d: R=2-F,6-OH 39e: R=4-OH 39f: R=2-OH
h
H2N
36
O
R N H
N
37
O N
R
O HO
e
N
HN
NH
O
NBn
35
34 HN
N
F
O
NBn
a
NHCbz
HN
32
CbzHN
O2N
N
F
31
NH
O
d
i NFmoc
42a: R=H 42b: R=2-Br 42c: R=3-Br 42d: R=4-Br 42e: R=2-F 42f: R=2-Cl 42g: R=2-NO2 42h: R=2-OMe 42i: R=2-iPr
NH
40a: R=4-F 40b: R=4-NH2 40c: R=2,6-diCl 40d: R=2-F,6-OH 40e: R=4-OH 40f: R=2-OH O
R N H
NH
43a: R=H 43b: R=2-Br 43c: R=3-Br 43d: R=4-Br 43e: R=2-F 43f: R=2-Cl 43g: R=2-NO2 43h: R=2-OMe 43i: R=2-iPr
Scheme 2. Reagents and conditions: (a) 1-benzylpiperidin-4-amine, K2CO3, DMF, 80 °C; (b) Fe, NH4Cl, THF/MeOH/water (1:2:2), 80 °C; (c) CDI, CH3CN; (d) 1-chloroethyl chloroformate, 1,2-dichloroethane, quant.; (e) H2, Pd/C, THF, EtOH, AcOH, 91%; (f) benzoic acid, BOP, iPr2NEt, CH2Cl2; (g) H2, Pd/C, THF; (h) aniline, BOP, iPr2NEt, CH2Cl2; (i) piperidine, DMF.
4953
A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954 Table 1 CCR3 inhibiting activity of urea derivatives 5–29
O
R
N H
N F
Compds
R
IC50 (nM)
Compds
Cl
N 5
780
F O
6
R
13
HN
59
N
Compds
62
21
7
N
N
N 51
22
N H
N
13
18
23
Br
N H
N
110
Cl
Cl
N
Br
N
O
N
N
52
16
1600
N H
24
O
O
N
O HN
N
15
Cl
9
Br
O
N 360
N
240
N
Cl
MeN
HN
N H
O
14
N
O 8
IC50 (nM)
O
N
OH O
R
Cl O
F
N
IC50 (nM)
O
44
920
O
N
N
N
N
17
440
25
HO
F
N H
N
13
F
HN
OH
N
O
O
O N
N
10
8.0
18
310
19
N 63
26
45
27
Cl
N H
N 29
H2N
O
O N
11
N
O
N
N
NO2
F O
O
O N
12
N
S 380
N H
20
N
N
4.9
N
31
N
30
O N
56
28
OMe
H2N
N H O
29
iPr
pharmacophore, these compounds showed the same value of IC50. An introduction of methyl substitution to the amide of 6 resulted in compound 7 (IC50 = 360 nM) with one sixth of the potency of 6. The left aromatic ring of 7 seemed to be out of the pharmacophore because of the methyl group. Substituents on the benzoimidazolone moiety were examined, and 5-amino derivative 37 showed sixfold potency compared with that of 8 (IC50 = 52 nM), but 4-fluoro 9 (IC50 = 44 nM) equal potency. Next, homopiperazine
N H
derivatives 11–15 and 17–20 were obtained as potent CCR3 antagonists. It seemed that the ortho-substituent of the aromatic ring was important for potency because benzamides 13 (IC50 = 62 nM), 14 (IC50 = 51 nM), and 18 (IC50 = 63 nM) were more effective than para-substituents 11 (IC50 = 310 nM), 12 (IC50 = 830 nM), and 17 (IC50 = 440 nM). A replacement of the homopiperazine moiety of 13 with the piperazine (16: IC50 = 1600 nM) resulted in a decline in inhibitory activity. The most potent homopiperazine derivative
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A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954
was 15 (IC50 = 18 nM) possessing a 2,6-dichlorobenzyl moiety. Lastly, benzamide proline moiety was examined. Introduction of bromo substitution to the phenyl group of 21 (IC50 = 240 nM) revealed most suitable substitution position for CCR3 inhibitory activity is 2-position (22: IC50 = 13 nM). Among various 2-substitutions (25–29) 2-nitrobenzamide proline derivative 27 was obtained with an IC50 value of 4.9 nM. The 2-nitrobenzamide 27 has 50-fold inhibitory activity compared with that of 21 unsubstituted. The inhibitory activity of 27 against CCR1, CCR2 and CCR5 resulted in no effect on them at 10 lM. In conclusion, to improve the CCR3 inhibitory activity of the lead compound 2 derived from the hit compound 1, a series of ureas were identified. The conversion of diphenylmethyl propyl piperidine moiety to 6-fluoronaphthyl methyl nortropane was critical for potent activity. The ortho-substituent on the aromatic ring of the left cyclic amine subunit was effective. Finally, the introduction of a nitro substituent at the 2-position of the benzamide moiety of the proline derivative led to the successful identification of 27, which is a selective CCR3 antagonist and the most potent in this series. We will report our additional efforts toward potent, selective and bioavailable CCR3 antagonists in due course. References and notes 1. Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony Lafontaine, J.; Godard, P. N. Engl. J. Med. 1990, 323, 1033. 2. Review: Pease, J. E.; Horuk, R. Expert Opin. Ther. Patents 2009, 19, 39. 3. Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Bioorg. Med. Chem. Lett. 2001, 11, 1219. 4. Batt, D. G.; Houghton, G. C.; Santella, J. B., III; Wacker, D. A.; Welch, P. K.; Orlovsky, Y. I.; Wadman, E. A.; Trzaskos, J. M.; Davies, P.; Decicco, C. P.; Carter, P. H. Bioorg. Med. Chem. Lett. 2005, 15, 787.
5. Varnes, J. G.; Gardner, D. S.; Santella, J. B., III; Duncia, J. V.; Estrella, M.; Watson, P. S.; Clark, C. M.; Ko, S. S.; Welch, P.; Covington, M.; Stowell, N.; Wadman, E.; Davies, P.; Solomon, K.; Newton, R. C.; Trainor, G. L.; Decicco, C. P.; Wacker, D. A. Bioorg. Med. Chem. Lett. 2004, 14, 1645. 6. Dhanak, D.; Christmann, L. T.; Darcy, M. G.; Jurewicz, A. J.; Keenan, R. M.; Lee, J.; Sarau, H. M.; Widdowson, K. L.; White, J. R. Bioorg. Med. Chem. Lett. 2001, 11, 1441. 7. Gong, L.; Hogg, J. H.; Collier, J.; Wilhelm, R. S.; Soderberg, C. Bioorg. Med. Chem. Lett. 2003, 131, 3597. 8. Ting, P. C.; Lee, J. F.; Wu, J.; Umland, S. P.; Aslanian, R.; Cao, J.; Dong, Y.; Garlisi, C. G.; Gilbert, E. J.; Huang, Y.; Jakway, J.; Kelly, J.; Liu, Z.; McCombie, S.; Shah, H.; Tian, F.; Wan, Y.; Shih, N. Y. Bioorg. Med. Chem. Lett. 2005, 15, 1375. 9. Anderskewitz, R.; Bauer, R.; Bodenbach, G.; Gester, D.; Gramlich, B.; Morschhauser, G.; Birke, F. Bioorg. Med. Chem. Lett. 2005, 15, 669. 10. Wacker, D. A.; Santella, J. B., III; Gardner, D. S.; Varnes, J. G.; Estrella, M.; DeLucca, G. V.; Ko, S. S.; Tanabe, K.; Watson, P. S.; Welch, P. K.; Covington, M.; Stowell, N.; Wadman, E.; Davies, P.; Solomon, K.; Newton, R. C.; Trainor, G. L.; Friedman, S. M.; Decicco, C. P.; Duncia, J. V. Bioorg. Med. Chem. Lett. 2002, 12, 1785. 11. De Lucca, G. V.; Kim, U. T.; Johnson, C.; Vargo, B. J.; Welch, P. K.; Covington, M.; Davies, P.; Solomon, K.; Newton, R. C.; Trainor, G. L.; Decicco, C. P.; Ko, S. S. J. Med. Chem. 2002, 45, 3794. 12. Sato, I.; Morihira, K.; Inami, H.; Kubota, H.; Morokata, T.; Suzuki, K.; Hamada, N.; Iura, Y.; Nitta, A.; Imaoka, T.; Takahashi, T.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2008, 16, 144. 13. Sato, I.; Morihira, K.; Inami, H.; Kubota, H.; Morokata, T.; Suzuki, K.; Iura, Y.; Nitta, A.; Imaoka, T.; Takahashi, T.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2008, 16, 8607. 14. Sato, I.; Morihira, K.; Inami, H.; Kubota, H.; Morokata, T.; Suzuki, K.; Ohno, K.; Iura, Y.; Nitta, A.; Imaoka, T.; Takahashi, T.; Takeuchi, M.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2009, 17, 5989. 15. Takahashi, T.; Imaoka, T.; Tanida, K.; Mori, N.; Kaneko, M.; Torii, Y.; World Patent Appl. WO 0034278. 16. For a description of the human CCR3 inhibitory activity assay, please see Ref. 17. 17. Takahashi, T.; Imaoka, T.; Tomioka, H.; Hatakeyama, D.; Nitta, A.; Kaneko, M.; Takizawa, S.; Torii, Y.; Morihira, K.; Morokata, T.; World Patent Appl. WO 0226708.
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
Discovery and structure–activity relationships of urea derivatives as potent and novel CCR3 antagonists Aiko Nitta a,⇑, Yosuke Iura a, Hiroki Tomioka a, Ippei Sato b, Koichiro Morihira b, Hirokazu Kubota b, Tatsuaki Morokata b, Makoto Takeuchi b, Mitsuaki Ohta b, Shin-ichi Tsukamoto b, Takayuki Imaoka a, Toshiya Takahashi a a b
Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 9 February 2012 Revised 6 June 2012 Accepted 13 June 2012 Available online 20 June 2012
The synthesis and structure–activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC50 = 190 nM) derived from initial screening hit compound 1 (IC50 = 600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC50 = 4.9 nM) as a potent CCR3 antagonist. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Allergic diseases CCR3 antagonists Urea derivatives Proline moiety
infiltration of eosinophils to inflammatory sites may have clinical potential in allergic diseases.2–11 A series of potent amide-based CCR3 antagonists possessing 6-fluoronaphthalenyl methyl moiety in our joint research project have been reported.12–14 During these studies, we also evaluated a series of urea derivatives for CCR3 inhibitory activity that display different structure–activity relationships from amides. In this Letter, we detail our efforts to discover the urea series of CCR3 antagonists. In our initial efforts to discover potential and selective CCR3 antagonists, screening of our corporate compound library yielded several hit compounds, including compound 1 as shown in Figure
The hallmark of allergic diseases such as asthma is selective accumulation of eosinophils at inflammatory sites.1 Therefore, eosinophils are thought to play an important role in the initiation and progression of these diseases. CC chemokine receptor 3 (CCR3), a member of the seven transmembrane G-protein coupled receptor (GPCR) family, is the receptor for eotaxin and appears predominantly on eosinophils. Upon activation, eosinophils release lipid mediators, cytotoxic proteins, oxygen metabolites and cytokines, all of which have potential to produce the clinically observed pathophysiology. A growing body of clinical studies and animal models suggest that eotaxin and CCR3 play a major role in allergic diseases and thus, a selective CCR3 antagonist that suppresses the
O
O N
N
N
N N
N N
N H
N
F 2: IC50 = 190 nM
1: IC50 = 600 nM
Figure 1. Screening hit compound 1 and modified lead compound 2.
⇑ Corresponding author. Tel.: +81 467 32 9659; fax: +81 467 32 9891. E-mail address: [email protected] (A. Nitta). 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.06.042
4952
A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954
1.15 Compound 1 showed unique structural features such as tricyclic imidazolo-quinazolone and diphenylmethyl piperidine moieties and moderate inhibitory activity for CCR3 (IC50 = 600 nM). To elevate CCR3 inhibitory activity and avoid synthetic difficulty and low bioavailability of 1,16 various derivatives were synthesized. As a result, tetrahydroisoquinoline urea derivative 2 (IC50 = 190 nM) was discovered as a lead compound. The inhibitory activity of 2 against other CC chemokine receptors, CCR1, CCR2 and CCR5, was also evaluated and it resulted in no effect on them at a concentration of 10 lM. Toward optimization of the new lead compound 2, we decided to modify the linker structure of 2, which showed a length suitable for CCR3 inhibitory activity but was too flexible. To design a rigid linker, the substructure of another lead compound 3 was utilized for adjusting the positions of both terminal aromatics and central tertiary amine.12 As shown in Figure 2, therefore, the diphenylmethyl propyl piperidine moiety of 2 was converted to 6-fluoronaphthyl methyl nortropane. Moreover, the tetrahydroisoquinoline was replaced with various cyclic amines in the left part. As shown in Scheme 1, the 6-fluoro-naphthyl methyl nortropane derivatives were synthesized by activation of nortropane amine 4 with 4-nitrophenyl chloroformate,13 followed by condensation with commercially available or appropriate amines that were prepared by common routes described in Scheme 2. 6-Fluoro-1,2,3,4-tetrahydroisoquinoline, a starting material for synthesis of 5 was prepared as reported.17 The CCR3 inhibitory activity data for selected compounds are listed in Table 1. Compound 5 (IC50 = 780 nM) possessing the substructure of 2 was not effective with one-quarter of the potency of 2. As it seemed that the left aromatic ring of compounds 6 (IC50 = 59 nM) and 8 (IC50 = 52 nM) was located as the same
suitable positions of right and left aromatics
suitable length but flexible linker O
fluorine atom N
N H
F
N 2
tertiary amine
O N H
N F
rigid linker 3: IC50 = 20 nM
O N
N H
N F
Figure 2. Important pharmacophores for CCR3 inhibitory activity and new compound design. O H2N
a, b N
4
R
N H
N
F
F
5-29
Scheme 1. Reagents and conditions: (a) ClCO2p-NO2Ph, NaHCO3, CHCl3; (b) amine, Et3N, CHCl3.
NBn
O
F
NBn
a
O2N
F F
NO2
30
b, c HN
N H
F
NO2
b, c
N H
33
CbzHN O N
f
38
NFmoc
41
HN
Cl
N
g
N
R Cl
39a: R=4-F 39b: R=4-NH2 39c: R=2,6-diCl 39d: R=2-F,6-OH 39e: R=4-OH 39f: R=2-OH
h
H2N
36
O
R N H
N
37
O N
R
O HO
e
N
HN
NH
O
NBn
35
34 HN
N
F
O
NBn
a
NHCbz
HN
32
CbzHN
O2N
N
F
31
NH
O
d
i NFmoc
42a: R=H 42b: R=2-Br 42c: R=3-Br 42d: R=4-Br 42e: R=2-F 42f: R=2-Cl 42g: R=2-NO2 42h: R=2-OMe 42i: R=2-iPr
NH
40a: R=4-F 40b: R=4-NH2 40c: R=2,6-diCl 40d: R=2-F,6-OH 40e: R=4-OH 40f: R=2-OH O
R N H
NH
43a: R=H 43b: R=2-Br 43c: R=3-Br 43d: R=4-Br 43e: R=2-F 43f: R=2-Cl 43g: R=2-NO2 43h: R=2-OMe 43i: R=2-iPr
Scheme 2. Reagents and conditions: (a) 1-benzylpiperidin-4-amine, K2CO3, DMF, 80 °C; (b) Fe, NH4Cl, THF/MeOH/water (1:2:2), 80 °C; (c) CDI, CH3CN; (d) 1-chloroethyl chloroformate, 1,2-dichloroethane, quant.; (e) H2, Pd/C, THF, EtOH, AcOH, 91%; (f) benzoic acid, BOP, iPr2NEt, CH2Cl2; (g) H2, Pd/C, THF; (h) aniline, BOP, iPr2NEt, CH2Cl2; (i) piperidine, DMF.
4953
A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954 Table 1 CCR3 inhibiting activity of urea derivatives 5–29
O
R
N H
N F
Compds
R
IC50 (nM)
Compds
Cl
N 5
780
F O
6
R
13
HN
59
N
Compds
62
21
7
N
N
N 51
22
N H
N
13
18
23
Br
N H
N
110
Cl
Cl
N
Br
N
O
N
N
52
16
1600
N H
24
O
O
N
O HN
N
15
Cl
9
Br
O
N 360
N
240
N
Cl
MeN
HN
N H
O
14
N
O 8
IC50 (nM)
O
N
OH O
R
Cl O
F
N
IC50 (nM)
O
44
920
O
N
N
N
N
17
440
25
HO
F
N H
N
13
F
HN
OH
N
O
O
O N
N
10
8.0
18
310
19
N 63
26
45
27
Cl
N H
N 29
H2N
O
O N
11
N
O
N
N
NO2
F O
O
O N
12
N
S 380
N H
20
N
N
4.9
N
31
N
30
O N
56
28
OMe
H2N
N H O
29
iPr
pharmacophore, these compounds showed the same value of IC50. An introduction of methyl substitution to the amide of 6 resulted in compound 7 (IC50 = 360 nM) with one sixth of the potency of 6. The left aromatic ring of 7 seemed to be out of the pharmacophore because of the methyl group. Substituents on the benzoimidazolone moiety were examined, and 5-amino derivative 37 showed sixfold potency compared with that of 8 (IC50 = 52 nM), but 4-fluoro 9 (IC50 = 44 nM) equal potency. Next, homopiperazine
N H
derivatives 11–15 and 17–20 were obtained as potent CCR3 antagonists. It seemed that the ortho-substituent of the aromatic ring was important for potency because benzamides 13 (IC50 = 62 nM), 14 (IC50 = 51 nM), and 18 (IC50 = 63 nM) were more effective than para-substituents 11 (IC50 = 310 nM), 12 (IC50 = 830 nM), and 17 (IC50 = 440 nM). A replacement of the homopiperazine moiety of 13 with the piperazine (16: IC50 = 1600 nM) resulted in a decline in inhibitory activity. The most potent homopiperazine derivative
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A. Nitta et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4951–4954
was 15 (IC50 = 18 nM) possessing a 2,6-dichlorobenzyl moiety. Lastly, benzamide proline moiety was examined. Introduction of bromo substitution to the phenyl group of 21 (IC50 = 240 nM) revealed most suitable substitution position for CCR3 inhibitory activity is 2-position (22: IC50 = 13 nM). Among various 2-substitutions (25–29) 2-nitrobenzamide proline derivative 27 was obtained with an IC50 value of 4.9 nM. The 2-nitrobenzamide 27 has 50-fold inhibitory activity compared with that of 21 unsubstituted. The inhibitory activity of 27 against CCR1, CCR2 and CCR5 resulted in no effect on them at 10 lM. In conclusion, to improve the CCR3 inhibitory activity of the lead compound 2 derived from the hit compound 1, a series of ureas were identified. The conversion of diphenylmethyl propyl piperidine moiety to 6-fluoronaphthyl methyl nortropane was critical for potent activity. The ortho-substituent on the aromatic ring of the left cyclic amine subunit was effective. Finally, the introduction of a nitro substituent at the 2-position of the benzamide moiety of the proline derivative led to the successful identification of 27, which is a selective CCR3 antagonist and the most potent in this series. We will report our additional efforts toward potent, selective and bioavailable CCR3 antagonists in due course. References and notes 1. Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony Lafontaine, J.; Godard, P. N. Engl. J. Med. 1990, 323, 1033. 2. Review: Pease, J. E.; Horuk, R. Expert Opin. Ther. Patents 2009, 19, 39. 3. Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Bioorg. Med. Chem. Lett. 2001, 11, 1219. 4. Batt, D. G.; Houghton, G. C.; Santella, J. B., III; Wacker, D. A.; Welch, P. K.; Orlovsky, Y. I.; Wadman, E. A.; Trzaskos, J. M.; Davies, P.; Decicco, C. P.; Carter, P. H. Bioorg. Med. Chem. Lett. 2005, 15, 787.
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