title: Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development.
abstract: Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaw
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Balu
authors.initials: B
authors.lastname: Balasubramanian
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bonacorsi
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Janet Caceres
authors.initials: JC
authors.lastname: Cortes
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Cao
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Decicco
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Animesh
authors.initials: A
authors.lastname: Goswami
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Guo
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hanson
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Maxwell
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Michaudel
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pudzianowski
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Shun
authors.initials: S
authors.lastname: Su
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Dawn
authors.initials: D
authors.lastname: Sun
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Adrienne A
authors.initials: AA
authors.lastname: Tymiak
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Vokits
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Ruth
authors.initials: R
authors.lastname: Wexler
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Dauh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Research and Development, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Rulin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
mesh_terms: D001686:Biological Phenomena; D000077144:Clopidogrel; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; C032727:piperidine; D000077144:Clopidogrel; D013988:Ticlopidine