- Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide
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Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4′-alkyl and 4′-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.
- Robinson, Ralph P.,Bartlett, Jeremy A.,Bertinato, Peter,Bessire, Andrew J.,Cosgrove, Judith,Foley, Patrick M.,Manion, Tara B.,Minich, Martha L.,Ramos, Brenda,Reese, Matthew R.,Schmahai, Theodore J.,Swick, Andrew G.,Tess, David A.,Vaz, Alfin,Wolford, Angela
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scheme or table
p. 4150 - 4154
(2011/08/06)
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- Safe and practical large-scale synthesis of 2-aminoquinoline-6-carboxylic acid benzyl ester
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An efficient three-step sequence has been developed for the synthesis of 2-aminoquinoline-6-carboxylic acid benzyl ester starting from commercially available 6-quinolinecarboxylic acid. The process features a novel and exceptionally mild conversion of a q
- Couturier, Michel,Le, Tung
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p. 534 - 538
(2012/12/22)
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- SUBSTITUTED QUINOLINE COMPOUNDS
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This invention relates to MTP/Apo-B secretion inhibitors of Formula (I) wherein R1-R7, X1, m and n are as defined in the specification, as well as pharmaceutical compositions comprising the compounds, and methods of use of the compounds and compositions. The compounds of the invention are useful in treating obesity and associated diseases, conditions or disorders.
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Page/Page column 83
(2008/06/13)
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