title: Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors.
abstract: Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: April
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Brewer
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daniels
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Cornelia J
authors.initials: CJ
authors.lastname: Forster
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gilmore
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Monish
authors.initials: M
authors.lastname: Jain
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kanter
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Youngshin
authors.initials: Y
authors.lastname: Kwak
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Li
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Les
authors.initials: L
authors.lastname: McQuire
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Streeper
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Szklennik
authors.affiliation: Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003958:Diamide / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D003958:Diamide; D051048:Diacylglycerol O-Acyltransferase
keywords: 1,2,4-Triazole; DGAT1 inhibitors; Diamide compounds; Oral bioavailability; Triglyceride