Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1)

  • Bioorg Med Chem Lett. 2011 Nov 15;21(22):6693-8. doi: 10.1016/j.bmcl.2011.09.058.
Shung C Wu  1 ,  David Yoon ,  Janice Chin ,  Katy van Kirk ,  Ramakrishna Seethala ,  Rajasree Golla ,  Bin He ,  Thomas Harrity ,  Lori K Kunselman ,  Nathan N Morgan ,  Randolph P Ponticiello ,  Joseph R Taylor ,  Rachel Zebo ,  Timothy W Harper ,  Wenying Li ,  Mengmeng Wang ,  Lisa Zhang ,  Bogdan G Sleczka ,  Akbar Nayeem ,  Steven Sheriff ,  Daniel M Camac ,  Paul E Morin ,  John G Everlof ,  Yi-Xin Li ,  Cheryl A Ferraro ,  Kasia Kieltyka ,  Wilson Shou ,  Marianne B Vath ,  Tatyana A Zvyaga ,  David A Gordon ,  Jeffrey A Robl
Affiliations
  • 1. Bristol-Myers Squibb Research & Development, PO Box 5400, Hopewell, NJ 08534-5400, USA. [email protected]
PMID: 21983444 DOI: 10.1016/j.bmcl.2011.09.058
Abstract

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.