Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists.
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 13a Ki = 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).
Chemistry, School of Environmental & Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia. amcclusk@mail.newcastle.edu.au
Adam
A
McCluskey
Paul A
PA
Keller
Jody
J
Morgan
James
J
Garner
D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism
D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; C030986:pyrimidine