title: Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.
abstract: A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, United States.
authors.forename: Vince S C
authors.initials: VS
authors.lastname: Yeh
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Steven C
authors.initials: SC
authors.lastname: Cullen
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Madhup K
authors.initials: MK
authors.lastname: Dhaon
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Falls
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Nelson
authors.initials: N
authors.lastname: Grihalde
authors.forename: Philip
authors.initials: P
authors.lastname: Hajduk
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: King
authors.forename: Russel C
authors.initials: RC
authors.lastname: Klix
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Larson
authors.forename: Yau Y
authors.initials: YY
authors.lastname: Lau
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Scott W
authors.initials: SW
authors.lastname: Mittelstadt
authors.forename: Dan
authors.initials: D
authors.lastname: Plata
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rozema
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Stoner
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Voorbach
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Xili
authors.initials: X
authors.lastname: Xin
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D016208:Databases, Factual; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004285:Dogs; D005260:Female; D005289:Ferrets; D005772:Gastrointestinal Transit / Q000187:drug effects; D006367:HeLa Cells; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D019518:Postprandial Period; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood; D014839:Vomiting / Q000139:chemically induced
chemical_list: C572354:(4-(4-(7-aminopyrazolo(1,5-a)pyrimidin-6-yl)phenyl)cyclohexyl)acetic acid; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D014280:Triglycerides; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase