Benzyl ether structure-activity relationships in a series of ketopiperazine-based renin inhibitors

Noel A Powell; Emma H Clay; Daniel D Holsworth; John W Bryant; Michael J Ryan; Mehran Jalaie; Jeremy J Edmunds

doi:10.1016/j.bmcl.2005.07.063

Benzyl ether structure-activity relationships in a series of ketopiperazine-based renin inhibitors

Bioorg Med Chem Lett. 2005 Nov 1;15(21):4713-6. doi: 10.1016/j.bmcl.2005.07.063.

Authors

Noel A Powell¹, Emma H Clay, Daniel D Holsworth, John W Bryant, Michael J Ryan, Mehran Jalaie, Jeremy J Edmunds

Affiliation

¹ Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. [email protected]

PMID: 16143527
DOI: 10.1016/j.bmcl.2005.07.063

Abstract

Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.

MeSH terms

Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / pharmacokinetics
Caco-2 Cells
Cell Membrane Permeability
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Ether
Humans
Inhibitory Concentration 50
Piperazine
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics
Piperazines / pharmacology
Renin / antagonists & inhibitors*
Solubility
Structure-Activity Relationship

Substances

Antihypertensive Agents
Cytochrome P-450 Enzyme Inhibitors
Piperazines
Ether
Piperazine
CYP3A protein, human
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Renin