Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives as microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model

  • Bioorg Med Chem Lett. 2017 Jun 1;27(11):2594-2601. doi: 10.1016/j.bmcl.2017.03.068.
Nagarajan Muthukaman  1 ,  Macchindra Tambe  1 ,  Mahamadhanif Shaikh  1 ,  Dnyandeo Pisal  1 ,  Sanjay Deshmukh  1 ,  Shital Tondlekar  1 ,  Neelam Sarode  1 ,  Lakshminarayana Narayana  1 ,  Jitendra M Gajera  1 ,  Vidya G Kattige  2 ,  Srinivasa Honnegowda  2 ,  Vikas Karande  2 ,  Abhay Kulkarni  2 ,  Dayanidhi Behera  3 ,  Satyawan B Jadhav  3 ,  Girish S Gudi  3 ,  Neelima Khairatkar-Joshi  2 ,  Laxmikant A Gharat  4
Affiliations
  • 1. Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
  • 2. Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
  • 3. Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India.
  • 4. Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India. Electronic address: [email protected].
PMID: 28400234 DOI: 10.1016/j.bmcl.2017.03.068
Abstract

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig Pain model.

Keywords
Arachidonic acid; Aryl imidazole; Hyperalgesia; PGE(2); Rheumatoid arthritis; mPGES-1 inhibitor.