Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)

  • ACS Med Chem Lett. 2014 May 22;5(7):803-8. doi: 10.1021/ml500144h.
Jun Li  1 ,  Lawrence J Kennedy  1 ,  Haixia Wang  1 ,  James J Li  1 ,  Steven J Walker  1 ,  Zhenqiu Hong  1 ,  Stephen P O'Connor  1 ,  Akbar Nayeem  1 ,  Daniel M Camac  2 ,  Paul E Morin  2 ,  Steven Sheriff  2 ,  Mengmeng Wang  1 ,  Timothy Harper  1 ,  Rajasree Golla  1 ,  Ramakrishna Seethala  1 ,  Thomas Harrity  1 ,  Randolph P Ponticiello  1 ,  Nathan N Morgan  1 ,  Joseph R Taylor  1 ,  Rachel Zebo  1 ,  David A Gordon  1 ,  Jeffrey A Robl  1
Affiliations
  • 1. Department of Medicinal Chemistry, Department of Biology, Lead Evaluation, CADD, Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb , Bldg 13, Princeton, New Jersey 08543-5400, United States.
  • 2. Protein Science & Structure, Research & Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.
PMID: 25050169 DOI: 10.1021/ml500144h
Abstract

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

Keywords
Enzyme inhibitors; human 11β-hydroxysteroid dehydrogenase-type 1; triazolopyridines.
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