2. Academic Validation
  3. Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

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

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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