title: Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119.
abstract: A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
authors.affiliation: Departments of Medicinal Chemistry, Discovery Biology, Drug Metabolism, and Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.
authors.forename: Etzer
authors.initials: E
authors.lastname: Darout
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.forename: Matthew
authors.initials: M
authors.lastname: Corbett
authors.forename: Bryan
authors.initials: B
authors.lastname: Li
authors.forename: Andrei
authors.initials: A
authors.lastname: Shavnya
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Andrews
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Qifang
authors.initials: Q
authors.lastname: Li
authors.forename: Martha L
authors.initials: ML
authors.lastname: Minich
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bahnck
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonin
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelius
authors.forename: Ruduan
authors.initials: R
authors.lastname: Wang
authors.forename: Victoria
authors.initials: V
authors.lastname: Bagdasarian
authors.forename: Colleen P
authors.initials: CP
authors.lastname: Sobota
authors.forename: Sam
authors.initials: S
authors.lastname: Hornby
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Masterson
authors.forename: Reena M
authors.initials: RM
authors.lastname: Joseph
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D043822:Cyclodecanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D001952:Bridged-Ring Compounds; D043822:Cyclodecanes; C519854:GPR119 protein, human; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled