title: Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity.
abstract: We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.
authors.affiliation: Department of Medicinal chemistry, Laboratoire GlaxoSmithKline, 25-27 Avenue du Québec, 91951 Les Ulis, France. marie-helene.fouchet@gsk.com
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Fouchet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Donche
authors.forename: Christelle
authors.initials: C
authors.lastname: Martin
authors.forename: Anne
authors.initials: A
authors.lastname: Bouillot
authors.forename: Christophe
authors.initials: C
authors.lastname: Junot
authors.forename: Anne-Bénédicte
authors.initials: AB
authors.lastname: Boullay
authors.forename: Florent
authors.initials: F
authors.lastname: Potvain
authors.forename: Sylvie Demaria
authors.initials: SD
authors.lastname: Magny
authors.forename: Hervé
authors.initials: H
authors.lastname: Coste
authors.forename: Max
authors.initials: M
authors.lastname: Walker
authors.forename: Marc
authors.initials: M
authors.lastname: Issandou
authors.forename: Nérina
authors.initials: N
authors.lastname: Dodic
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D050171:Dyslipidemias / Q000139:chemically induced / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D005123:Eye / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010080:Oxazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D010879:Piperazines / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010880:Piperidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010080:Oxazoles; D010879:Piperazines; D010880:Piperidines; C107350:BIBB 515; D019751:Intramolecular Transferases; C021924:lanosterol synthase