title: Discovery of selective biaryl ethers as PDE10A inhibitors: improvement in potency and mitigation of Pgp-mediated efflux.
abstract: We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. rrzasa@amgen.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.forename: Shannon
authors.initials: S
authors.lastname: Rumfelt
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: James R
authors.initials: JR
authors.lastname: Falsey
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
authors.forename: Adrie D
authors.initials: AD
authors.lastname: Jones
authors.forename: Amy
authors.initials: A
authors.lastname: Porter
authors.forename: Steven W
authors.initials: SW
authors.lastname: Louie
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhao
authors.forename: James J S
authors.initials: JJ
authors.lastname: Treanor
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004987:Ethers; D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases