Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.

Autor: Kung DW; Worldwide Medicinal Chemistry, Groton, CT 06340, United States. Electronic address: daniel.w.kung@pfizer.com., Griffith DA; Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States. Electronic address: david.a.griffith@pfizer.com., Esler WP; Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge, MA 02139, United States., Vajdos FF; Structural Biology, Groton, CT 06340, United States., Mathiowetz AM; Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States., Doran SD; Pharmacokinetics, Dynamics and Metabolism, Groton, CT 06340, United States., Amor PA; Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge, MA 02139, United States., Bagley SW; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Banks T; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Cabral S; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Ford K; Primary Pharmacology Group, Groton, CT 06340, United States., Garcia-Irizarry CN; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Landis MS; Pharmaceutical Sciences Research Formulations, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States., Loomis K; Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States., McPherson K; Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States., Niosi M; Pharmacokinetics, Dynamics and Metabolism, Groton, CT 06340, United States., Rockwell KL; Primary Pharmacology Group, Groton, CT 06340, United States., Rose C; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Smith AC; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Southers JA; Worldwide Medicinal Chemistry, Groton, CT 06340, United States., Tapley S; Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Groton, CT 06340, United States., Tu M; Worldwide Medicinal Chemistry, Cambridge, MA 02139, United States., Valentine JJ; Primary Pharmacology Group, Groton, CT 06340, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Nov 15; Vol. 25 (22), pp. 5352-6. Date of Electronic Publication: 2015 Sep 15.
DOI: 10.1016/j.bmcl.2015.09.035
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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