Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability

J J Plattner; P A Marcotte; H D Kleinert; H H Stein; J Greer; G Bolis; A K Fung; B A Bopp; J R Luly; H L Sham

doi:10.1021/jm00120a006

Renin inhibitors. Dipeptide analogues of angiotensinogen utilizing a structurally modified phenylalanine residue to impart proteolytic stability

J Med Chem. 1988 Dec;31(12):2277-88. doi: 10.1021/jm00120a006.

Authors

J J Plattner¹, P A Marcotte, H D Kleinert, H H Stein, J Greer, G Bolis, A K Fung, B A Bopp, J R Luly, H L Sham, et al.

Affiliation

¹ Abbott Laboratories, Pharmaceutical Discovery Division, Abbott Park, Illinois 60064.

PMID: 3143010
DOI: 10.1021/jm00120a006

Abstract

A series of renin inhibitors have been prepared and evaluated for their susceptibility to cleavage by the serine protease chymotrypsin. The compounds were designed by consideration of the structural requirements in the active-site region of renin and chymotrypsin. By systematic alteration of the P3 phenylalanine residue, compounds with varying degrees of renin inhibitory potency and chymotrypsin susceptibility were obtained. Selected analogues from this group were examined in vivo for both their hypotensive effects and metabolic patterns.

Publication types

Comparative Study

MeSH terms

Angiotensinogen / analogs & derivatives*
Animals
Binding Sites
Blood Pressure / drug effects
Chemical Phenomena
Chemistry
Chymotrypsin
Dipeptides / chemical synthesis*
Dipeptides / pharmacokinetics
Dipeptides / pharmacology
Drug Design
Drug Stability
Ethylene Glycols / chemical synthesis*
Ethylene Glycols / pharmacokinetics
Ethylene Glycols / pharmacology
Haplorhini
Humans
Phenylalanine / analogs & derivatives*
Rats
Renin / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Dipeptides
Ethylene Glycols
Angiotensinogen
Phenylalanine
Chymotrypsin
Renin