Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

  • ACS Med Chem Lett. 2011 Aug 9;2(10):747-51. doi: 10.1021/ml200137x.
Lanqi Jia  1 ,  Robert D Simpson  1 ,  Jing Yuan  1 ,  Zhenrong Xu  1 ,  Wei Zhao  1 ,  Salvacion Cacatian  1 ,  Colin M Tice  1 ,  Joan Guo  1 ,  Alexey Ishchenko  1 ,  Suresh B Singh  1 ,  Zhongren Wu  1 ,  Brian M McKeever  1 ,  Yuri Bukhtiyarov  1 ,  Judith A Johnson  1 ,  Christopher P Doe  2 ,  Richard K Harrison  1 ,  Gerard M McGeehan  1 ,  Lawrence W Dillard  1 ,  John J Baldwin  1 ,  David A Claremon  1
Affiliations
  • 1. Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, United States.
  • 2. GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
PMID: 24900262 DOI: 10.1021/ml200137x
Abstract

Structure guided optimization of a series of nonpeptidic alkyl amine Renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Keywords
Renin; aspartyl protease; hypertension; structure-based drug design.
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