Non-Peptide Corticotropin-Releasing Hormone Antagonists: Syntheses and Structure−Activity Relationships of 2-Anilinopyrimidines and -triazines

Abstract

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 hCRH₁K_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.