title: Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists.
abstract: A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.
authors.affiliation: Department of Chemical and Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Eman M
authors.initials: EM
authors.lastname: Eldemenky
authors.forename: Gil
authors.initials: G
authors.lastname: Ma
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Andrew D
authors.initials: AD
authors.lastname: White
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jones
authors.forename: Boshan
authors.initials: B
authors.lastname: Li
authors.forename: Sang-Phyo
authors.initials: SP
authors.lastname: Hong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001384:Azetidines; D007211:Indoles; C491208:MCHR1 protein, rat; D017481:Receptors, Somatostatin; C030374:indole