title: Spirolactam-based acetyl-CoA carboxylase inhibitors: toward improved metabolic stability of a chromanone lead structure.
abstract: Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.
authors: Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: David A
authors: DA
authors: Griffith
authors: Robert L
authors: RL
authors: Dow
authors: Kim
authors: K
authors: Huard
authors: David J
authors: DJ
authors: Edmonds
authors: Scott W
authors: SW
authors: Bagley
authors: Jana
authors: J
authors: Polivkova
authors: Dongxiang
authors: D
authors: Zeng
authors: Carmen N
authors: CN
authors: Garcia-Irizarry
authors: James A
authors: JA
authors: Southers
authors: William
authors: W
authors: Esler
authors: Paul
authors: P
authors: Amor
authors: Kathrine
authors: K
authors: Loomis
authors: Kirk
authors: K
authors: McPherson
authors: Kevin B
authors: KB
authors: Bahnck
authors: Cathy
authors: C
authors: Préville
authors: Tereece
authors: T
authors: Banks
authors: Dianna E
authors: DE
authors: Moore
authors: Alan M
authors: AM
authors: Mathiowetz
authors: Elnaz
authors: E
authors: Menhaji-Klotz
authors: Aaron C
authors: AC
authors: Smith
authors: Shawn D
authors: SD
authors: Doran
authors: David A
authors: DA
authors: Beebe
authors: Matthew F
authors: MF
authors: Dunn
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy
chemical_list: D007769:Lactams; D000103:Acetyl-CoA Carboxylase