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

Shung C Wu; 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

doi:10.1016/j.bmcl.2011.09.058

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. Epub 2011 Sep 21.

Affiliation

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.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
Animals
Cell Line
Diabetes Mellitus, Type 2 / drug therapy
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Humans
Isoquinolines / chemistry*
Isoquinolines / pharmacokinetics
Isoquinolines / pharmacology*
Mice
Mice, Inbred BALB C
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Isoquinolines
11-beta-Hydroxysteroid Dehydrogenase Type 1