Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.

@article{Walker2013SynthesisAB,
  title={Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.},
  author={Daniel P. Walker and Graciela B. Arhancet and Hwang-Fun Lu and Steven E. Heasley and Suzanne Metz and Natasha M. Kablaoui and Francisco M Franco and Cathleen Elizabeth Hanau and Jeffrey A. Scholten and John R Springer and Yvette M. Fobian and Jeffrey S. Carter and Li Xing and Shengtian Yang and Alexander F Shaffer and Gina M. Jerome and Michael T. Baratta and William M. Moore and Michael L. Vazquez},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2013},
  volume={23 4},
  pages={
          1120-6
        }
}
Microsomal prostaglandin E(2) 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… Expand
Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1.
This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increasedExpand
RATIONAL DESIGN, SYNTHESIS, AND CHARACTERIZATION OF NOVEL mPGES-1 INHIBITORS AS NEXT GENERATION OF ANTI-INFLAMMATORY DRUGS
TLDR
In general, a library of compounds are identified as potent mPGES-1 inhibitors without significant inhibition against COXs, which will help to suppress inflammation induced PGE2 production and exert anti-inflammatory activity while avoid the side effects ofCOXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events. Expand
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.
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 wereExpand
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.
TLDR
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, and selected mPGes-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability. Expand
Selective inhibitors of human mPGES-1 from structure-based computational screening.
TLDR
The computationally modeled binding structures of these new inhibitors of mPGES-1 provide some interesting clues for rational design of modified structures of the inhibitors to more favorably bind with mPGes-1. Expand
Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions.
TLDR
This perspective introduces mPGES-1 as a key player within the network of eicosanoid biosynthesis and summarizes the current understanding of its structure and mechanism, and presents high-throughput and in silico screening techniques. Expand
Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs
TLDR
Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE2 (an inflammatory marker) levels compared to the currently available drug celecoxib. Expand
Targeting microsomal prostaglandin E2 synthase-1 (mPGES-1): the development of inhibitors as an alternative to non-steroidal anti-inflammatory drugs (NSAIDs)
Prostaglandin E2 (PGE2) is an important substance in diverse human organs and regulates a variety of physiological and pathological processes, such as inflammation, fever, pain and cancer. MicrosomalExpand
Chemistry and biology of microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors as novel anti-inflammatory agents: recent developments and current status
Prostaglandin (PG) E2, a key mediator of inflammatory pain and fever, is biosynthesized from PGH2 by microsomal prostaglandin E2 synthase-1 (mPGES-1). During inflammation the expression of mPGES-1Expand
Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold
In recent years, the emergence of biologically active compounds that contain a heterocyclic ring has gained a great deal of attention among medicinal chemists. Among these, benzoxazole-basedExpand
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