Human glucagon receptor antagonists based on alkylidene hydrazides.
A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic experiments showed fast clearance of most of the compounds tested. A representative compound [4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide] with an IC50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.
Ling
Anthony
A
Pfizer Global Research and Development, 10770 Science Center Dr., San Diego, CA 92121, USA. anthony.ling@agouron.com
Plewe
Michael
M
Gonzalez
Javier
J
Madsen
Peter
P
Sams
Christian K
CK
Lau
Jesper
J
Gregor
Vlad
V
Murphy
Doug
D
Teston
Kimberly
K
Kuki
Atsuo
A
Shi
Shenghua
S
Truesdale
Larry
L
Kiel
Dan
D
May
John
J
Lakis
James
J
Anderes
Kenna
K
Iatsimirskaia
Eugenia
E
Sidelmann
Ulla G
UG
Knudsen
Lotte B
LB
Brand
Christian L
CL
Polinsky
Alex
A
D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D007267:Injections; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D006834:Hydrazines; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon