ABSTRACT
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.
Subject(s)
Amides/pharmacology , Boronic Acids/pharmacology , Pyrazoles/pharmacology , Tetrazoles/pharmacology , Thrombin/antagonists & inhibitors , Thrombin/chemistry , Triazoles/pharmacology , Amides/chemistry , Binding Sites , Boronic Acids/chemistry , Crystallography, X-Ray , Indicators and Reagents , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Stereoisomerism , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity. It is now widely recognized that there are at least two distinct Ang II receptor subtypes. AT1 receptors are selective in their recognition of agents such as losartan, DuP 532, L-158,809, SK&F108566, and similar non-peptides. To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor. Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated. Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydrosioquinoline-3-carboxylic acids which have selective affinity for AT2 receptors. The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.
