title: Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor.
abstract: The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
authors: Departments of Medicinal Chemistry, Discovery Biology, Drug Metabolism and Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340, United States. kim.f.mcclure@pfizer.com
authors: Kim F
authors: KF
authors: McClure
authors: Margaret
authors: M
authors: Jackson
authors: Kimberly O
authors: KO
authors: Cameron
authors: Daniel W
authors: DW
authors: Kung
authors: David A
authors: DA
authors: Perry
authors: Suvi T M
authors: ST
authors: Orr
authors: Yingxin
authors: Y
authors: Zhang
authors: Jeffrey
authors: J
authors: Kohrt
authors: Meihua
authors: M
authors: Tu
authors: Hua
authors: H
authors: Gao
authors: Dilinie
authors: D
authors: Fernando
authors: Ryan
authors: R
authors: Jones
authors: Noe
authors: N
authors: Erasga
authors: Guoqiang
authors: G
authors: Wang
authors: Jana
authors: J
authors: Polivkova
authors: Wenhua
authors: W
authors: Jiao
authors: Roger
authors: R
authors: Swartz
authors: Hirokazu
authors: H
authors: Ueno
authors: Samit K
authors: SK
authors: Bhattacharya
authors: Ingrid A
authors: IA
authors: Stock
authors: Sam
authors: S
authors: Varma
authors: Victoria
authors: V
authors: Bagdasarian
authors: Sylvie
authors: S
authors: Perez
authors: Dawn
authors: D
authors: Kelly-Sullivan
authors: Ruduan
authors: R
authors: Wang
authors: Jimmy
authors: J
authors: Kong
authors: Peter
authors: P
authors: Cornelius
authors: Laura
authors: L
authors: Michael
authors: Eunsun
authors: E
authors: Lee
authors: Ann
authors: A
authors: Janssen
authors: Stefanus J
authors: SJ
authors: Steyn
authors: Kimberly
authors: K
authors: Lapham
authors: Theunis
authors: T
authors: Goosen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002490:Central Nervous System / Q000187:drug effects*; D054314:Drug Inverse Agonism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007536:Isomerism; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D007189:Indans; D054440:Receptors, Ghrelin
keywords: Antagonist; Ghrelin; Inverse agonist; Muscarinic; Receptor; Receptor occupancy