Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design

  • Bioorg Med Chem Lett. 2010 Feb 1;20(3):881-6. doi: 10.1016/j.bmcl.2009.12.082.
Colin M Tice  1 ,  Wei Zhao ,  Zhenrong Xu ,  Salvacion T Cacatian ,  Robert D Simpson ,  Yuan-Jie Ye ,  Suresh B Singh ,  Brian M McKeever ,  Peter Lindblom ,  Joan Guo ,  Paula M Krosky ,  Barbara A Kruk ,  Jennifer Berbaum ,  Richard K Harrison ,  Judith J Johnson ,  Yuri Bukhtiyarov ,  Reshma Panemangalore ,  Boyd B Scott ,  Yi Zhao ,  Joseph G Bruno ,  Linghang Zhuang ,  Gerard M McGeehan ,  Wei He ,  David A Claremon
Affiliations
  • 1. Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.
PMID: 20064717 DOI: 10.1016/j.bmcl.2009.12.082
Abstract

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.

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