title: Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors.
abstract: The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4.
authors.affiliation: Department of Medicinal Chemistry, Piramal Life Sciences Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India.
authors.forename: Hashim
authors.initials: H
authors.lastname: Motiwala
authors.forename: Shivaji
authors.initials: S
authors.lastname: Kandre
authors.forename: Vishal
authors.initials: V
authors.lastname: Birar
authors.forename: Kishorkumar S
authors.initials: KS
authors.lastname: Kadam
authors.forename: Atish
authors.initials: A
authors.lastname: Rodge
authors.forename: Ravindra D
authors.initials: RD
authors.lastname: Jadhav
authors.forename: M
authors.initials: M
authors.lastname: Mahesh Kumar Reddy
authors.forename: Manoja K
authors.initials: MK
authors.lastname: Brahma
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.forename: Lalit
authors.initials: L
authors.lastname: Doshi
authors.forename: Amol
authors.initials: A
authors.lastname: Gupte
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Gangopadhyay
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.forename: Shaila
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Mamta
authors.initials: M
authors.lastname: Sharma
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D058990:Molecular Targeted Therapy; D009765:Obesity; D011725:Pyridines / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D014280:Triglycerides; D014508:Urea; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase