Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite

David N Deaton; Enoch N Gao; Kevin P Graham; Jeffrey W Gross; Aaron B Miller; John M Strelow

doi:10.1016/j.bmcl.2007.11.048

Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite

Bioorg Med Chem Lett. 2008 Jan 15;18(2):732-7. doi: 10.1016/j.bmcl.2007.11.048. Epub 2007 Nov 19.

Authors

David N Deaton¹, Enoch N Gao, Kevin P Graham, Jeffrey W Gross, Aaron B Miller, John M Strelow

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. david.n.deaton@gsk.com

Abstract

Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.

MeSH terms

Angiotensin-Converting Enzyme 2
Angiotensin-Converting Enzyme Inhibitors / chemistry*
Angiotensin-Converting Enzyme Inhibitors / metabolism
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Animals
Female
Male
Mice
Mice, Inbred C57BL
Peptidyl-Dipeptidase A / drug effects*
Peptidyl-Dipeptidase A / genetics
Structure-Activity Relationship
Substrate Specificity
Sulfhydryl Compounds / chemistry*
Sulfhydryl Compounds / metabolism
Sulfhydryl Compounds / pharmacology

Substances

Angiotensin-Converting Enzyme Inhibitors
Sulfhydryl Compounds
Peptidyl-Dipeptidase A
Ace2 protein, mouse
Angiotensin-Converting Enzyme 2