Journal of Medicinal Chemistry p. 805 - 818 (1999)
Update date:2022-07-30
Topics:
Arvanitis, Argyrios G.
Gilligan, Paul J.
Chorvat, Robert J.
Cheeseman, Robert S.
Christos, Thomas E.
Bakthavatchalam, Rajagopal
Beck, James P.
Cocuzza, Anthony J.
Hobbs, Frank W.
Wilde, Richard G.
Arnold, Charles
Chidester, Dennis
Curry, Matthew
He, Liqi
Hollis, Andrea
Klaczkiewicz, John
Krenitsky, Paul J.
Rescinito, Joseph P.
Scholfield, Everett
Culp, Steven
De Souza, Errol B.
Fitzgerald, Lawrence
Grigoriadis, Dimitri
Tam, S. William
Wong, Y. Nancy
Huang, Shiew-Mei
Shen, Helen L.
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 [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist α-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 α-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 hCRH1 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 hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1)K(1) = 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.
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