Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists.
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.
Letourneau
Jeffrey J
JJ
Ligand Pharmaceuticals, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA. jletourneau@ligand.com
Riviello
Christopher M
CM
Li
Hong
H
Cole
Andrew G
AG
Ho
Koc-Kan
KK
Zanetakos
Heather A
HA
Desai
Hema
H
Zhao
Jiuqiao
J
Auld
Douglas S
DS
Napier
Susan E
SE
Thomson
Fiona J
FJ
Goan
Katharine A
KA
Morphy
J Richard
JR
Ohlmeyer
Michael H J
MH
Webb
Maria L
ML
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003866:Depressive Disorder / Q000188:drug therapy; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017483:Receptors, Vasopressin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000081:Acetamides; D065092:Antidiuretic Hormone Receptor Antagonists; D011799:Quinazolines; D017483:Receptors, Vasopressin; C030686:acetamide