Non-peptide corticotropin-releasing hormone antagonists: Syntheses and structure-activity relationships of 2-anilinopyrimidines and -triazines

被引：72

作者：

Arvanitis, AG ^{[1
]}

Gilligan, PJ ^{[1
]}

Chorvat, RJ ^{[1
]}

Cheeseman, RS ^{[1
]}

Christos, TE ^{[1
]}

Bakthavatchalam, R ^{[1
]}

Beck, JP ^{[1
]}

Cocuzza, AJ ^{[1
]}

Hobbs, FW ^{[1
]}

Wilde, RG ^{[1
]}

Arnold, C ^{[1
]}

Chidester, D ^{[1
]}

Curry, M ^{[1
]}

He, LQ ^{[1
]}

Hollis, A ^{[1
]}

Klaczkiewicz, J ^{[1
]}

Krenitsky, PJ ^{[1
]}

Rescinito, JP ^{[1
]}

Scholfield, E ^{[1
]}

Culp, S ^{[1
]}

De Souza, EB ^{[1
]}

Fitzgerald, L ^{[1
]}

Grigoriadis, D ^{[1
]}

Tam, SW ^{[1
]}

Wong, YN ^{[1
]}

Huang, SM ^{[1
]}

Shen, HL ^{[1
]}

机构：

[1] Dupont Merck Pharmaceut Co, Expt Stn, Dept Chem & Phys Sci, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 05期

关键词：

D O I：

10.1021/jm980222w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [I-125]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (K-i = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than a-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH(1) receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH(1) receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1) K-i = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.

引用

页码：805 / 818

页数：14

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