title: Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor.
abstract: DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.
authors.affiliation: PharmaTherapeutics Research & Development, Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, United States. robert.l.dow@pfizer.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Andrews
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Michael Gibbs
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Laperle
authors.forename: Qifang
authors.initials: Q
authors.lastname: Li
authors.forename: Dawn
authors.initials: D
authors.lastname: Mather
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.forename: Christian
authors.initials: C
authors.lastname: Perreault
authors.forename: Susan
authors.initials: S
authors.lastname: Tapley
authors.forename: William J
authors.initials: WJ
authors.lastname: Zavadoski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy; D010069:Oxadiazoles / Q000737:chemistry; D010077:Oxazepines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010077:Oxazepines; C582730:PF-04620110; D051048:Diacylglycerol O-Acyltransferase
keywords: Carboxylic acid bioisotere; DGAT-1; Diabetes; Obesity; Passive permeability; Polar surface area