title: Stereoselective synthesis of a MCHr1 antagonist.
abstract: Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.
authors.affiliation: Chemistry Process Research and Development, Amgen Inc., Thousand Oaks, California 19320, USA. danders555@yahoo.com
authors.forename: Denise
authors.initials: D
authors.lastname: Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Storz
authors.forename: Pingli
authors.initials: P
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.forename: Pingchen
authors.initials: P
authors.lastname: Fan
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Chen
authors.forename: Alan
authors.initials: A
authors.lastname: Allgeier
authors.forename: Alain
authors.initials: A
authors.lastname: Burgos
authors.forename: Jason
authors.initials: J
authors.lastname: Tedrow
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Rich
authors.initials: R
authors.lastname: Crockett
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Rashid
authors.initials: R
authors.lastname: Syed
authors.forename: Robert D
authors.initials: RD
authors.lastname: Larsen
authors.forename: Mike
authors.initials: M
authors.lastname: Martinelli
mesh_terms: D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: C526481:AMG 076; D001557:Benzenesulfonates; D003509:Cyclohexanecarboxylic Acids; D007546:Isoquinolines; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin