title: Development of potent and selective small-molecule human Urotensin-II antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. jeff.j.mcatee@gsk.com
authors.forename: John J
authors.initials: JJ
authors.lastname: McAtee
authors.forename: Jason W
authors.initials: JW
authors.lastname: Dodson
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dowdell
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Girard
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hilfiker
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: Deyou
authors.initials: D
authors.lastname: Sha
authors.forename: Gren Z
authors.initials: GZ
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Andrew Q
authors.initials: AQ
authors.lastname: Viet
authors.forename: Daohua
authors.initials: D
authors.lastname: Zhang
authors.forename: Nambi V
authors.initials: NV
authors.lastname: Aiyar
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Luz H
authors.initials: LH
authors.lastname: Carballo
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Evans
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Fries
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethke
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.forename: Catherine C K
authors.initials: CC
authors.lastname: Yuan
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Neeb
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D008970:Molecular Weight; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C530869:(3,4-dichlorophenyl)methyl(2-oxo-2-(3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl)ethyl)amine; D000814:Aniline Compounds; D010881:Piperidones; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; C121697:UTS2R protein, human