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

Organic & Biomolecular Chemistry Pub Date: 2003-08-22 DOI: 10.1039/B305458F

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 13aKi = 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).

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