Details

Autor(en) / Beteiligte

• Jia, Lanqi
• Simpson, Robert D
• Yuan, Jing
• Xu, Zhenrong
• Zhao, Wei
• Cacatian, Salvacion
• Tice, Colin M
• Guo, Joan
• Ishchenko, Alexey
• Singh, Suresh B
• Wu, Zhongren
• McKeever, Brian M
• Bukhtiyarov, Yuri
• Johnson, Judith A
• Doe, Christopher P
• Harrison, Richard K
• McGeehan, Gerard M
• Dillard, Lawrence W
• Baldwin, John J
• Claremon, David A

Titel

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

Ist Teil von

• ACS medicinal chemistry letters, 2011-10, Vol.2 (10), p.747-751

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.