Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists |
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Authors: | McCluskey Adam Keller Paul A Morgan Jody Garner James |
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Institution: | Chemistry, School of Environmental & Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia. amcclusk@mail.newcastle.edu.au |
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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 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). |
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