title: Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability.
abstract: The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259.
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. v.chudasama@ucl.ac.uk s.caddick@ucl.ac.uk.
authors.forename: Eifion
authors.initials: E
authors.lastname: Robinson
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. v.chudasama@ucl.ac.uk s.caddick@ucl.ac.uk.
authors.forename: Emily
authors.initials: E
authors.lastname: Knight
authors.affiliation: Centre for Inflammation and Tissue Repair, 5 University Street, London WC1E 6JJ, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Smoktunowicz
authors.affiliation: Centre for Inflammation and Tissue Repair, 5 University Street, London WC1E 6JJ, UK.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.affiliation: GSK, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Inglis
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. v.chudasama@ucl.ac.uk s.caddick@ucl.ac.uk.
authors.forename: Vijay
authors.initials: V
authors.lastname: Chudasama
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. v.chudasama@ucl.ac.uk s.caddick@ucl.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Caddick
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008968:Molecular Conformation; D044463:Receptor, PAR-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: D007191:Indazoles; C424723:RWJ 58259; D044463:Receptor, PAR-1; D014508:Urea; D010975:Platelet Aggregation Inhibitors