title: 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.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, CT 06340, USA. ralph.p.robinson@pfizer.com
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Bartlett
authors.forename: Peter
authors.initials: P
authors.lastname: Bertinato
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bessire
authors.forename: Judith
authors.initials: J
authors.lastname: Cosgrove
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Foley
authors.forename: Tara B
authors.initials: TB
authors.lastname: Manion
authors.forename: Martha L
authors.initials: ML
authors.lastname: Minich
authors.forename: Brenda
authors.initials: B
authors.lastname: Ramos
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Schmahai
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Swick
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.forename: Alfin
authors.initials: A
authors.lastname: Vaz
authors.forename: Angela
authors.initials: A
authors.lastname: Wolford
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002219:Carbamates / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D002219:Carbamates; D002352:Carrier Proteins; D007211:Indoles; C561923:PF 02575799; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C521290:dirlotapide