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Human glucagon receptor antagonists based on alkylidene hydrazides |
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| Authors: | Ling Anthony Plewe Michael Gonzalez Javier Madsen Peter Sams Christian K Lau Jesper Gregor Vlad Murphy Doug Teston Kimberly Kuki Atsuo Shi Shenghua Truesdale Larry Kiel Dan May John Lakis James Anderes Kenna Iatsimirskaia Eugenia Sidelmann Ulla G Knudsen Lotte B Brand Christian L Polinsky Alex |
| Affiliation: | Pfizer Global Research and Development, 10770 Science Center Dr., San Diego, CA 92121, USA. anthony.ling@agouron.com |
| Abstract: | 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. |
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