title: Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.
abstract: Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
authors.affiliation: Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India. pradipks@drreddys.com
authors.forename: Sanjita
authors.initials: S
authors.lastname: Sasmal
authors.forename: Gade
authors.initials: G
authors.lastname: Balaji
authors.forename: Hariprasada R
authors.initials: HR
authors.lastname: Kanna Reddy
authors.forename: D
authors.initials: D
authors.lastname: Balasubrahmanyam
authors.forename: Gujjary
authors.initials: G
authors.lastname: Srinivas
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Kyasa
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Sasmal
authors.forename: Ish
authors.initials: I
authors.lastname: Khanna
authors.forename: Rashmi
authors.initials: R
authors.lastname: Talwar
authors.forename: J
authors.initials: J
authors.lastname: Suresh
authors.forename: Vikram P
authors.initials: VP
authors.lastname: Jadhav
authors.forename: Syed
authors.initials: S
authors.lastname: Muzeeb
authors.forename: Dhanya
authors.initials: D
authors.lastname: Shashikumar
authors.forename: K
authors.initials: K
authors.lastname: Harinder Reddy
authors.forename: V J
authors.initials: VJ
authors.lastname: Sebastian
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rist
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Elster
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C103263:MCHR1 protein, human; D011799:Quinazolines; D011979:Receptors, Pituitary Hormone; D017481:Receptors, Somatostatin; C092274:melanin-concentrating hormone receptor