Bioorganic and Medicinal Chemistry Letters p. 3500 - 3503 (2008)
Update date:2022-07-29
Topics:
McAtee, John J.
Dodson, Jason W.
Dowdell, Sarah E.
Girard, Gerald R.
Goodman, Krista B.
Hilfiker, Mark A.
Sehon, Clark A.
Sha, Deyou
Wang, Gren Z.
Wang, Ning
Viet, Andrew Q.
Zhang, Daohua
Aiyar, Nambi V.
Behm, David J.
Carballo, Luz H.
Evans, Christopher A.
Fries, Harvey E.
Nagilla, Rakesh
Roethke, Theresa J.
Xu, Xiaoping
Yuan, Catherine C.K.
Douglas, Stephen A.
Neeb, Michael J.
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.
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