title: Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core.
abstract: A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3mg/kg.
authors: Pfizer Global Research and Development, Groton, CT 06340, USA. robert.l.dow@pfizer.com
authors: Robert L
authors: RL
authors: Dow
authors: Melissa
authors: M
authors: Andrews
authors: Gary E
authors: GE
authors: Aspnes
authors: Gayatri
authors: G
authors: Balan
authors: E
authors: E
authors: Michael Gibbs
authors: Angel
authors: A
authors: Guzman-Perez
authors: Kapil
authors: K
authors: Karki
authors: Jennifer L
authors: JL
authors: Laperle
authors: Jian-Cheng
authors: JC
authors: Li
authors: John
authors: J
authors: Litchfield
authors: Michael J
authors: MJ
authors: Munchhof
authors: Christian
authors: C
authors: Perreault
authors: Leena
authors: L
authors: Patel
mesh_terms: D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010077:Oxazepines; C582730:PF-04620110; D011743:Pyrimidines; D014280:Triglycerides; D051048:Diacylglycerol O-Acyltransferase