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Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a , a close analogue of the screening hit, potently inhibited PTGES in vitro , displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies. [ABSTRACT FROM AUTHOR]

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5 , an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC 80 of 24 nM for inhibition of PGE 2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC 80 in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours. [ABSTRACT FROM AUTHOR]

Here we report on novel, potent 3,3-dimethyl substituted N -aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE 2 synthesis in an ex vivo human whole blood (HWB) assay with an IC 50 of 7 nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30 μM, and failed to inhibit human mPGES-2 at 62.5 μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE 2 . In dog, 14 had oral bioavailability (74%), clearance (3.62 mL/(min*kg)) and volume of distribution ( V d,ss = 1.6 L/kg) values within our target ranges. For these reasons, 14 was selected for further study. [ABSTRACT FROM AUTHOR]

Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC 50 = 5700 nM against PGE 2 production), for a potent suppressor of PGE 2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC 50 values of 4.5 and 6.9 nM, respectively, against LPS-induced PGE 2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC 50 = 70 nM) than MK-886 and hit compound 1 , respectively. Molecular docking suggests that compound 8n could inhibit PGE 2 production by blocking the PGH 2 binding site of human mPGES-1 enzyme. [ABSTRACT FROM AUTHOR]

[Display omitted] • The genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 production and dopaminergic neurodegeneration. • Compound 7s, a mPGES-1 inhibitor, exhibited potent neuroprotective activity against 6-OHDA-induced toxicity in PC12 cells. • Compound 7s (MPO-0144) as a small molecule could be a promising therapeutic agent for PD. • Compound 7s ameliorated motor impairments and dopaminergic neuronal damage in animal model of PD. mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE 2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE 2 IC 50 = 41.77 nM; mPGES-1 IC 50 = 1.16 nM) exhibited a potent neuroprotection (ED 50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC 50 = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients. [ABSTRACT FROM AUTHOR]

mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE 2 . Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3 H )-one, pyrido[4,3- d ]pyrimidin-4(3 H )-one and pyrido[2,3- d ]pyrimidin-4(3 H )-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs ( 28 , 48 , 49 ) were identified with <10 nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE 2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib. [ABSTRACT FROM AUTHOR]

Abstract: Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors. [Copyright &y& Elsevier]

Abstract: A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018μM) and PGE-2 inhibition in a cell-based assay (0.034μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7h half-life. [Copyright &y& Elsevier]

Abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH2 to PGE2 and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC50 of 1.1μM) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10μM concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors. [Copyright &y& Elsevier]

Abstract: Human microsomal prostaglandin E synthase-1 (mPGES-1) is an emerging drug target for inflammatory disorders and cancer suppression. Therefore, it is crucially important to discover mPGES-1 inhibitors with novel structural scaffolds for the development of anti-inflammatory drugs. Here, we report the mPGES-1 inhibitors identified through screening of a chemical library. Initial screening of 1841 compounds out of 200,000 in a master library resulted in 9 primary hits. From the master library, 387 compounds that share the scaffold structure with the 9 primary hit compounds were selected, of which 3 compounds showed strong inhibitory activity against mPGES-1 having IC50 values of 1–3μM. Notably, a derivative of sulfonylhydrazide, compound 3b, inhibited the LPS-induced PGE2 production in RAW 264.7 cells. This compound showed novel scaffold structure compared to the known inhibitors of mPGES-1, suggesting that it could be further developed as a potent mPGES-1 inhibitor. [Copyright &y& Elsevier]

Abstract: The imidazoquinoline derivative 1 was found as a novel mPGES-1 inhibitor. Optimization of 1 led to the identification of the 2-chlorophenyl group at the C(2)-position and the quinolone structure at the C(4)-position. Compound 33, the most potent synthesized compound, showed excellent mPGES-1 inhibition (IC50 =9.1nM) with high selectivity (>1000-fold) over both COX-1 and COX-2. [Copyright &y& Elsevier]

Abstract: A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC50 of 0.34μM) and in human whole blood assay (IC50 of 2.1μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors. [Copyright &y& Elsevier]

Abstract: Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1=0.94μM; IC50 5-LO=0.1μM) showing the most favorable in vitro pharmacological profile. [Copyright &y& Elsevier]

Abstract: Microsomal prostaglandin E2 synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE2 production in enzymatic and cell-based assays. The synthesis of these molecules and their activities will be discussed. [Copyright &y& Elsevier]

Abstract: Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14μM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. [Copyright &y& Elsevier]

Abstract: Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC50 of 0.42μM (50% FBS) and a human whole blood IC50 of 1.3μM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100mg/kg. [Copyright &y& Elsevier]