Identification of alkylidene hydrazides as glucagon receptor antagonists.
High throughput screening of our small molecule combinatorial library identified a class of benzoylnaphthalenehydrazones with modest affinity for the human glucagon receptor. Optimization of this initial hit through a series of targeted libraries and traditional medicinal chemistry led to ligands with nanomolar affinities. Pharmacological evaluation demonstrated that these ligands were competitive glucagon receptor antagonists. Intravenous administration of a representative benzoylnaphthalenehydrazone into rats attenuated glucagon-stimulated glucose levels.
Ling
A
A
Department of Medicinal Chemistry, Pfizer Global Research and Development, La Jolla/Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. anthony.ling@agouron.com
Hong
Y
Y
Gonzalez
J
J
Gregor
V
V
Polinsky
A
A
Kuki
A
A
Shi
S
S
Teston
K
K
Murphy
D
D
Porter
J
J
Kiel
D
D
Lakis
J
J
Anderes
K
K
May
J
J
Knudsen
L B
LB
Lau
J
J
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D000242:Cyclic AMP / Q000096:biosynthesis; D005934:Glucagon / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C435934:3-chloro-4-hydroxy-N'-((4-hydroxy-1-naphthyl)methylidene)benzohydrazide; D001549:Benzamides; D001786:Blood Glucose; D006835:Hydrazones; D018027:Receptors, Glucagon; D005934:Glucagon; D000242:Cyclic AMP