2. Academic Validation
  3. 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

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

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: Laxmikant.gharat@glenmarkpharma.com.
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.

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