title: Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.
abstract: GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.
authors.affiliation: GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. skatamreddy@nc.rr.com
authors.forename: Subba R
authors.initials: SR
authors.lastname: Katamreddy
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carpenter
authors.forename: Carina E
authors.initials: CE
authors.lastname: Ammala
authors.forename: Eric E
authors.initials: EE
authors.lastname: Boros
authors.forename: Ron L
authors.initials: RL
authors.lastname: Brashear
authors.forename: Celia P
authors.initials: CP
authors.lastname: Briscoe
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Bullard
authors.forename: Richard D
authors.initials: RD
authors.lastname: Caldwell
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Conlee
authors.forename: Dallas K
authors.initials: DK
authors.lastname: Croom
authors.forename: Shane M
authors.initials: SM
authors.lastname: Hart
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Heyer
authors.forename: Paul R
authors.initials: PR
authors.lastname: Johnson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kashatus
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Minick
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Peckham
authors.forename: Sean A
authors.initials: SA
authors.lastname: Ross
authors.forename: Shane G
authors.initials: SG
authors.lastname: Roller
authors.forename: Vicente A
authors.initials: VA
authors.lastname: Samano
authors.forename: Howard R
authors.initials: HR
authors.lastname: Sauls
authors.forename: Sarva M
authors.initials: SM
authors.lastname: Tadepalli
authors.forename: James B
authors.initials: JB
authors.lastname: Thompson
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.forename: James M
authors.initials: JM
authors.lastname: Way
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D003106:Colon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D054795:Incretins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C578804:1-methylethyl 4-((7-(2-fluoro-4-(methylsulfonyl)phenyl)-6,7-dihydro-5H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)-1-piperidinecarboxylate; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D054795:Incretins; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D005947:Glucose