1190319-99-3Relevant articles and documents
Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting
Huard, Kim,Smith, Aaron C.,Cappon, Gregg,Dow, Robert L.,Edmonds, David J.,El-Kattan, Ayman,Esler, William P.,Fernando, Dilinie P.,Griffith, David A.,Kalgutkar, Amit S.,Ross, Trenton T.,Bagley, Scott W.,Beebe, David,Bi, Yi-An,Cabral, Shawn,Crowley, Collin,Doran, Shawn D.,Dowling, Matthew S.,Liras, Spiros,Mascitti, Vincent,Niosi, Mark,Pfefferkorn, Jeffrey A.,Polivkova, Jana,Préville, Cathy,Price, David A.,Shavnya, Andre,Shirai, Norimitsu,Smith, Andrew H.,Southers, James R.,Tess, David A.,Thuma, Benjamin A.,Varma, Manthena V.,Yang, Xiaojing
, p. 10879 - 10896 (2020/11/09)
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.
SUBSTITUTED ACETYL-COA CARBOXYLASE INHIBITORS
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Page/Page column 24, (2012/11/07)
The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein G is R1, R2 and R3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal.
N2-PYRAZOLOSPIROKETONE ACETYL-COA CARBOXYLASE INHIBITORS
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, (2011/06/16)
The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, R3 and R4 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl- CoA carboxylase enzyme(s) in an animal.
