Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting.

Autor:	Huard K; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Smith AC; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Cappon G; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Dow RL; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Edmonds DJ; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., El-Kattan A; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Esler WP; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Fernando DP; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Griffith DA; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Kalgutkar AS; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Ross TT; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Bagley SW; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Beebe D; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Bi YA; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Cabral S; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Crowley C; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Doran SD; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Dowling MS; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Liras S; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Mascitti V; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Niosi M; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Pfefferkorn JA; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Polivkova J; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Préville C; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Price DA; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Shavnya A; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Shirai N; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Smith AH; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Southers JR; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Tess DA; Pfizer Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139, United States., Thuma BA; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Varma MV; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States., Yang X; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Oct 08; Vol. 63 (19), pp. 10879-10896. Date of Electronic Publication: 2020 Sep 18.
DOI:	10.1021/acs.jmedchem.0c00640
Abstrakt:	Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 ( 12 ), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.
Databáze:	MEDLINE
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