title: Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure.
abstract: Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats.
authors.affiliation: Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397 Biberach, Germany. joerg.kley@boehringer-ingelheim.com,
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Kley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mack
authors.forename: Bradford
authors.initials: B
authors.lastname: Hamilton
authors.forename: Stefan
authors.initials: S
authors.lastname: Scheuerer
authors.forename: Norbert
authors.initials: N
authors.lastname: Redemann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D018938:Caco-2 Cells; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D006801:Humans; D007031:Hypothalamus; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D010539:Permeability; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C571364:BI 99179; D001583:Benzoxazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011392:Proline; D064429:Fatty Acid Synthases