title: Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation.
abstract: A series of chiral lactam carboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 μM/kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 h and points to its excellent bioavailability. The compounds 31a (IC50 = 6.6 μM) and 32a (IC50 = 37 μM), as well as their racemic mixture 28i (IC50 = 16 μM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50 = 3.3 μM) and U46619 (IC50 = 2.7 μM) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: K S
authors.initials: KS
authors.lastname: Anil Kumar
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Misra
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Tanveer Irshad
authors.initials: TI
authors.lastname: Siddiqi
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Stuti
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Jain
authors.affiliation: Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Rabi Sankar
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Barthwal
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India. Electronic address: madhu_dikshit@cdri.res.in.
authors.forename: Madhu
authors.initials: M
authors.lastname: Dikshit
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India. Electronic address: dk_dikshit@cdri.res.in.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Dikshit
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D003094:Collagen
keywords: Aminomethylpiperidine; Antiplatelet; Collagen; Epinephrine; Pyroglutamic acid; Thrombosis