Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series – Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2 Nagarajan Muthukaman a , Sanjay Deshmukh a , Macchindra Tambe a , Dnyandeo Pisal a , Shital Tondlekar a , Mahamadhanif Shaikh a , Neelam Sarode a , Vidya G. Kattige b , Pooja Sawant b , Monali Pisat b , Vikas Karande b , Srinivasa Honnegowda b , Abhay Kulkarni b , Dayanidhi Behera c , Satyawan B. Jadhav c , Ramchandra R. Sangana c , Girish S. Gudi c , Neelima Khairatkar-Joshi b , Laxmikant A. Gharat a,⇑ a Chemical Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India b Biological Research, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India c Drug Metabolism and Pharmacokinetics, Glenmark Pharmaceuticals Limited, Glenmark Research Center, Navi Mumbai, Maharashtra 400709, India article info Article history: Received 17 January 2018 Revised 26 February 2018 Accepted 26 February 2018 Available online xxxx Keywords: Rheumatoid arthritis Bioavailability Lipophilicity PGE 2 Thromboxane A Hyperalgesia Osteoarthritic pain abstract In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were per- formed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160–950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selec- tivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead com- pounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X recep- tor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED 50 : 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED 50 : 106 mg/kg). Ó 2018 Elsevier Ltd. All rights reserved. Microsomal PGE synthase-1 (mPGES-1) is a dominant source of biologically active PGE 2 , during the biosynthesis in the down- stream of the COXs in arachidonic acid (AA) pathway. PGES is a ter- minal enzyme, which is classified into three isoforms, namely microsomal PGES-1 (mPGES-1), microsomal PGES-2 (mPGES-2) and cytosolic PGES (cPGES). 1 The role of prostaglandins (PGs) in inflammatory pain is well established. Binding of PGs to prostanoid receptors (EP1, EP2, EP3 and EP4) sensitizes pain specific neurons to stimulate pain in central nociceptive systems and mPGES-1 expression was strongly up-regulated in the brain and spinal cord during inflammation. 2 An inducible enzyme mPGES-1, which is functionally coupled to COX-2, is responsible for the release of PGE 2 in response to inflammatory stimuli, such as IL-1b, TNF-a, and LPS. A previous study by Akira group has shown that PGE 2 pro- duction by LPS is completely suppressed in peritoneal macro- phages derived from mPGES-1 knockout mice. 3 This enabled the use of mPGES-1 knockout mice as models for various diseases, such as collagen induced arthritis, pain hypersensitivity and neuro- pathic pain. 4 An mPGES-1 knockout study in mice exhibits re- diversion of the PGH 2 substrate by a PG synthases into several prostanoids (PGF 2a , PGD 2 and PGI 2 ), including PGE 2 and thrombox- ane A 2 (TXA 2 ). 4 Therefore, it is expected that mPGES-1 inhibitors may not increase the risk of cardiovascular side effects associated with COX-2 inhibitor, as they do not inhibit PGI 2 production. 5 Sim- ilarly, additional knockout studies demonstrated devoid of gas- trointestinal and renal toxicity, which are associated with COX-1 inhibitors. 6 Further, these knockout animals revealed viable, fertile, and normal phenotype, which signifies that mPGES-1 inhibitors could possess anti-inflammatory potential with minimum or neg- ligible side effect profile. 4 Therefore, selective inhibition of mPGES-1 might be a promising approach for the design of an effec- tive anti-inflammatory drugs lacking NSAID related side effects. 7 https://doi.org/10.1016/j.bmcl.2018.02.048 0960-894X/Ó 2018 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: Laxmikant.gharat@glenmarkpharma.com (L.A. Gharat). Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Please cite this article in press as: Muthukaman N., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.048