title: 3-Oxo-hexahydro-1H-isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors.
abstract: Bicyclic chiral scaffolds are privileged motifs in medicinal chemistry. Over the years, we have reported covalent bicyclic prolyl oligopeptidase inhibitors that were highly selective for POP over a number of homologous proteins. Herein, we wish to report the structure-based design and synthesis of a novel class of POP inhibitors based on hexahydroisoindoles. A docking study guided the selection of structures for synthesis. The stereochemistry, decoration, and position within the molecule of the bicyclic scaffolds were assessed virtually. Following the synthesis of the best candidates, in vitro assays revealed that one member of this chemical series was more active than any of our previous inhibitors with a Ki of 1.0 nM. Additional assays also showed that the scaffold of this potent inhibitor, in contrast to one of our previously reported chemical series, is highly metabolically stable, despite the foreseen potential sites of metabolism. Interestingly, computer docking calculations accurately predicted the optimal features of the inhibitors.
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Mariaule
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Cesco
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Airaghi
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Kurian
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Paolo
authors.initials: P
authors.lastname: Schiavini
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rocheleau
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Huskić
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mittermaier
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D054833:Isoindoles; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases