Ketopiperazine-based renin inhibitors: optimization of the "C" ring

Daniel D Holsworth; Cuiman Cai; Xue-Min Cheng; Wayne L Cody; Dennis M Downing; Noe Erasga; Chitase Lee; Noel A Powell; Jeremy J Edmunds; Michael Stier; Mehran Jalaie; Erli Zhang; Pat McConnell; Michael J Ryan; John Bryant; Tingsheng Li; Aparna Kasani; Eric Hall; Rajendra Subedi; Mohammad Rahim; Samarendra Maiti

doi:10.1016/j.bmcl.2006.01.084

Ketopiperazine-based renin inhibitors: optimization of the "C" ring

Bioorg Med Chem Lett. 2006 May 1;16(9):2500-4. doi: 10.1016/j.bmcl.2006.01.084. Epub 2006 Feb 15.

Affiliation

¹ Pfizer Global Research and Development, Michigan Laboratories, Department of Chemistry, Ann Arbor, MI 48105, USA. Daniel.Holsworth@pfizer.com

PMID: 16480874
DOI: 10.1016/j.bmcl.2006.01.084

Abstract

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.

MeSH terms

Crystallography, X-Ray
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology*
Renin / antagonists & inhibitors*
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Piperazines
Cytochrome P-450 Enzyme System
CYP3A protein, human
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Renin