4Q1N

Structure-based design of 4-hydroxy-3,5-substituted piperidines as direct renin inhibitors

Summary for 4Q1N

• Entry DOI: 10.2210/pdb4q1n/pdb
• Related: 4PYV
• Descriptor: Renin, DIMETHYL SULFOXIDE, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: aspartic protease, angiotensin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76255.07

Authors

Schiering, N.,D'Arcy, A.,Irie, O.,Yokokawa, F. (deposition date: 2014-04-04, release date: 2014-08-06, Last modification date: 2024-10-09)

Primary citation

Ehara, T.,Irie, O.,Kosaka, T.,Kanazawa, T.,Breitenstein, W.,Grosche, P.,Ostermann, N.,Suzuki, M.,Kawakami, S.,Konishi, K.,Hitomi, Y.,Toyao, A.,Gunji, H.,Cumin, F.,Schiering, N.,Wagner, T.,Rigel, D.F.,Webb, R.L.,Maibaum, J.,Yokokawa, F.
Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.
ACS Med Chem Lett, 5:787-792, 2014

PubMed Abstract: A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

PubMed: 25050166
DOI: 10.1021/ml500137b

Experimental method

X-RAY DIFFRACTION (2.09 Å)