title: Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.
abstract: A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 μM.
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States. Electronic address: daniel.w.kung@pfizer.com.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.affiliation: Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States. Electronic address: david.a.griffith@pfizer.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge, MA 02139, United States.
authors.forename: William P
authors.initials: WP
authors.lastname: Esler
authors.affiliation: Structural Biology, Groton, CT 06340, United States.
authors.forename: Felix F
authors.initials: FF
authors.lastname: Vajdos
authors.affiliation: Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Groton, CT 06340, United States.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Doran
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge, MA 02139, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Amor
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Tereece
authors.initials: T
authors.lastname: Banks
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Cabral
authors.affiliation: Primary Pharmacology Group, Groton, CT 06340, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ford
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Carmen N
authors.initials: CN
authors.lastname: Garcia-Irizarry
authors.affiliation: Pharmaceutical Sciences Research Formulations, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Landis
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Loomis
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States.
authors.forename: Kirk
authors.initials: K
authors.lastname: McPherson
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Groton, CT 06340, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.affiliation: Primary Pharmacology Group, Groton, CT 06340, United States.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Rockwell
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Rose
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: Worldwide Medicinal Chemistry, Groton, CT 06340, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Southers
authors.affiliation: Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Tapley
authors.affiliation: Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States.
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.affiliation: Primary Pharmacology Group, Groton, CT 06340, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Valentine
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013141:Spiro Compounds; D000105:Acetyl Coenzyme A; D000103:Acetyl-CoA Carboxylase
keywords: ACC; Acetyl CoA-carboxylase; Diamine; Spirocycle