Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists

Abstract

Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity >50 : 1 noted. All analogues were screened for their ability to interact with CRH₁ and CRH₂ receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH₂. However, several compounds were potent and selective CRH₁ antagonists, most notably 13aK_i = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH₁ pharmacophore (J. Med. Chem., 1999, 42, 2351–2357).