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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Pradip K Sasmal
  • C Vamsee Krishna
  • S Sudheerkumar Adabala
  • khaji Abdul Rawoof
  • Amima Thadi
  • K Pawan Sukumar
  • Srisailam Cheera
  • Chandrasekhar Abbineni
  • K V L Narasimha Rao
  • A Prasanthi
  • Kamal Nijhawan
  • Mahaboobi Jaleel
  • Lakshmi Ramachandran Iyer
  • T Krishna Chaitanya
  • Nirbhay Kumar Tiwari
  • N Lavanya Krishna
  • Vijay Potluri
  • Ish Khanna
  • Øystein Rist
  • Lisbeth Elster
  • Thomas Högberg

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.

OriginalsprogEngelsk
TidsskriftBioorganic & Medicinal Chemistry Letters
Vol/bind25
Udgave nummer4
Sider (fra-til)887-92
Antal sider6
ISSN0960-894X
DOI
StatusUdgivet - 15 feb. 2015

ID: 136854257