2. Academic Validation
  3. Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation

Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation

  • Eur J Med Chem. 2014 Jun 23:81:456-72. doi: 10.1016/j.ejmech.2014.05.017.
K S Anil Kumar 1,  Ankita Misra 2,  Tanveer Irshad Siddiqi 1,  Stuti Srivastava 1,  Manish Jain 2,  Rabi Sankar Bhatta 3,  Manoj Barthwal 2,  Madhu Dikshit 4,  Dinesh K Dikshit 5
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
  • 2 Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
  • 3 Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India.
  • 4 Pharmacology Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India. Electronic address: madhu_dikshit@cdri.res.in.
  • 5 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.
PMID: 24859764 DOI: 10.1016/j.ejmech.2014.05.017
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.

Keywords

Aminomethylpiperidine; Antiplatelet; Collagen; Epinephrine; Pyroglutamic acid; Thrombosis.

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