title: Discovery of pyrrolopyridazines as novel DGAT1 inhibitors.
abstract: A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 μM to 48 nM.
authors.affiliation: Amgen Inc., Amgen South San Francisco, South San Francisco, CA 94080, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.forename: Kiyosei
authors.initials: K
authors.lastname: Iio
authors.forename: Kexue
authors.initials: K
authors.lastname: Li
authors.forename: Rebeka
authors.initials: R
authors.lastname: Choi
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
authors.forename: Simon
authors.initials: S
authors.lastname: Jackson
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sagawa
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Yoshida
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
mesh_terms: D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1