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

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

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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