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
  • 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: [email protected].
  • 5. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sec-10, Janakipuram Ext., Sitapur Road, Lucknow 226 031, India. Electronic address: [email protected].
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.