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Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

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.

SUBMITTER: Ehara T

PROVIDER: S-EPMC4094259 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

Ehara Takeru T Irie Osamu O Kosaka Takatoshi T Kanazawa Takanori T Breitenstein Werner W Grosche Philipp P Ostermann Nils N Suzuki Masaki M Kawakami Shimpei S Konishi Kazuhide K Hitomi Yuko Y Toyao Atsushi A Gunji Hiroki H Cumin Frederic F Schiering Nikolaus N Wagner Trixie T Rigel Dean F DF Webb Randy L RL Maibaum Jürgen J Yokokawa Fumiaki F

ACS medicinal chemistry letters 20140421 7

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 t ...[more]

PMID: 25050166

Dataset Information

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

Publications

Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.

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