ABSTRACT
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Subject(s)
Acetamides/chemical synthesis , Antidiuretic Hormone Receptor Antagonists , Hypothalamo-Hypophyseal System/drug effects , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Acetamides/chemistry , Acetamides/pharmacology , Animals , Caco-2 Cells , Humans , Inhibitory Concentration 50 , Male , Molecular Structure , Quinazolinones/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Humans , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.
