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Discovery of microsomal triglyceride transfer protein (MTP) inhibitors with potential for decreased active metabolite load compared to dirlotapide.

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Robinson RP,Bartlett JA,Bertinato P,Bessire AJ,Cosgrove J,Foley PM,Manion TB,Minich ML,Ramos B,Reese MR,Schmahai TJ,Swick AG,Tess DA,Vaz A,Wolford A

doi

10.1016/j.bmcl.2011.05.099

subject

Has Abstract

pub_date

2011-07-15 00:00:00

pages

4150-4

issue

14

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)00740-2

journal_volume

21

pub_type

杂志文章

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