3Q5H

Clinically Useful Alkyl Amine Renin Inhibitors

Summary for 3Q5H

• Entry DOI: 10.2210/pdb3q5h/pdb
• Related: 3GW5 3KM4 3Q3T 3Q4B
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: aspartate protease, hypertension, renin expression, renin inhibitor, aspartyl protease, cleavage on pair of basic residues, disease mutation, glycoprotein, membrane, protease, secreted, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 76221.30

Authors

Wu, Z.,McKeever, B.M. (deposition date: 2010-12-28, release date: 2011-11-30, Last modification date: 2024-11-06)

Primary citation

Jia, L.,Simpson, R.D.,Yuan, J.,Xu, Z.,Zhao, W.,Cacatian, S.,Tice, C.M.,Guo, J.,Ishchenko, A.,Singh, S.B.,Wu, Z.,McKeever, B.M.,Bukhtiyarov, Y.,Johnson, J.A.,Doe, C.P.,Harrison, R.K.,McGeehan, G.M.,Dillard, L.W.,Baldwin, J.J.,Claremon, D.A.
Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
ACS Med Chem Lett, 2:747-751, 2011

PubMed 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.

PubMed: 24900262
DOI: 10.1021/ml200137x

Experimental method

X-RAY DIFFRACTION (2.16 Å)