title: Discovery of 6-phenylpyrimido[4,5-b][1,4]oxazines as potent and selective acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents.
abstract: The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Fox
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Kiyosei
authors.initials: K
authors.lastname: Iio
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Yoshida
authors.forename: Jian Ken
authors.initials: JK
authors.lastname: Zhang
authors.forename: Kexue
authors.initials: K
authors.lastname: Li
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.forename: Marc
authors.initials: M
authors.lastname: Labelle
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Smith
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rubenstein
authors.forename: Guosen
authors.initials: G
authors.lastname: Ye
authors.forename: Dustin
authors.initials: D
authors.lastname: McMinn
authors.forename: Simon
authors.initials: S
authors.lastname: Jackson
authors.forename: Rebekah
authors.initials: R
authors.lastname: Choi
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Shichang
authors.initials: S
authors.lastname: Miao
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsui
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ogawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Suzuki
authors.forename: Akio
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ozeki
authors.forename: Chihiro
authors.initials: C
authors.lastname: Okuma
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishii
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomimoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Furakawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Inaba
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sagawa
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D010078:Oxazines; D014280:Triglycerides; D051048:Diacylglycerol O-Acyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase