2. Academic Validation
  3. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

  • Bioorg Med Chem Lett. 2015 Feb 15;25(4):887-92. doi: 10.1016/j.bmcl.2014.12.064.
Pradip K Sasmal 1,  C Vamsee Krishna 2,  S Sudheerkumar Adabala 2,  M Roshaiah 2,  Khaji Abdul Rawoof 2,  Emima Thadi 2,  K Pavan Sukumar 2,  Srisailam Cheera 2,  Chandrasekhar Abbineni 2,  K V L Narasimha Rao 2,  A Prasanthi 2,  Kamal Nijhawan 2,  Mahaboobi Jaleel 2,  Lakshmi Ramachandran Iyer 2,  T Krishna Chaitanya 2,  Nirbhay Kumar Tiwari 2,  N Lavanya Krishna 2,  Vijay Potluri 2,  Ish Khanna 2,  Thomas M Frimurer 3,  Michael Lückmann 4,  Øystein Rist 5,  Lisbeth Elster 5,  Thomas Högberg 6
Affiliations

Affiliations

  • 1 Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India. Electronic address: pradipks@drreddys.com.
  • 2 Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India.
  • 3 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark; NNF, Center for Protein Research and NNF Center for Basic Metabolic Research, University of Copenhagen, Denmark.
  • 4 NNF, Center for Protein Research and NNF Center for Basic Metabolic Research, University of Copenhagen, Denmark.
  • 5 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
  • 6 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark. Electronic address: thomas.hogberg@leo-pharma.com.
PMID: 25599839 DOI: 10.1016/j.bmcl.2014.12.064
Abstract

Kappa Opioid Receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the Other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

Keywords

Anti-nociception; Benzimidazoles; KOR agonists; Kappa opioid receptor (KOR).

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