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

Screening of our chemical library using a rat corticotropin-releasing hormo ne (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [I-125]-0-Tyr-oCRH from rat frontal cortex homogenates whe n compared to the known peptide antagonist alpha-helical CRH(9-41) (K-i = 5 700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylat e cyclase activity in the same tissue, but it was less potent than a-helica l CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity rel ationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH(1) receptors. Several high-affini ty 2-anilinopyrimidines and -triazines were discovered, some of which had s uperior pharmacokinetic profiles in the rat. This paper describes the struc ture-activity studies which improved hCRH(1) receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1) K-i = 3 2 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 bioavaila bility at 5 mg/kg) relative to the early lead structures.