Author/Authors :
John J. McAtee، نويسنده , , Jason W. Dodson، نويسنده , , Sarah E. Dowdell، نويسنده , , Gerald R. Girard، نويسنده , , Krista B. Goodman، نويسنده , , Mark A. Hilfiker، نويسنده , , Clark A. Sehon، نويسنده , , DeYou Sha، نويسنده , , Gren Z. Wang، نويسنده , , Ning Wang، نويسنده , , Andrew Q. Viet، نويسنده , , Daohua Zhang ، نويسنده , , Nambi V. Aiyar، نويسنده , , David J. Behm، نويسنده , , Luz H. Carballo، نويسنده , , Christopher A. Evans، نويسنده , , Harvey E. Fries، نويسنده , , Rakesh Nagilla، نويسنده , , Theresa J. Roethke، نويسنده , , Xiaoping Xu، نويسنده , , et al.، نويسنده ,
Abstract :
This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.
Keywords :
Urotensin , hU-II , Antagonist , HUT , GPR14 , U-II
