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

  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},
  volume={23 4},
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
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.
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.
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.
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
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


Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template.
The SAR of a series of potent and selective mPGES-1 inhibitors based on an oxicam template that demonstrated low nanomolar mPGEs-1 inhibition in an enzyme assay and had over 238-fold selectivity for mPGes-1 over COX-2 and over 200-foldSelectivity formPGES -1 over 6-keto PGF(1alpha) is described. Expand
L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.
The design of L-735,524, a potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, is guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, and is currently in phase II human clinical trials. Expand
Inhibitors of the microsomal prostaglandin E(2) synthase-1 as alternative to non steroidal anti-inflammatory drugs (NSAIDs)--a critical review.
Current knowledge about synthetic and natural mPGES-1 inhibitors focusing on structural and mechanistic investigations is summarized and the therapeutic efficiency and safety is critically discussed on the basis of cellular and animal studies in which mPGes-1 activity was pharmacologically or genetically modulated. Expand
Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response.
It is shown that the agonist pharmacology in rat masks the important differences in human pharmacology for bridged piperidine compounds 8, 9, and 11. Expand
3-Substituted gem-cyclohexane sulfone based gamma-secretase inhibitors for Alzheimer's disease: conformational analysis and biological activity.
Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards theExpand
Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target
Differences in the kinetics of the expression of the two enzymes suggest distinct regulatory mechanisms for their expression of prostaglandin E2, indicating that mPGES-1 is a potential target for the development of therapeutic agents for treatment of several diseases. Expand
ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.
  • D. Kempf, K. Marsh, +7 authors X. Kong
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1995
It is demonstrated that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease with potent in vitro activity against laboratory and clinical strains of HIV. Expand
Bioactivation of carboxylic acid compounds by UDP-Glucuronosyltransferases to DNA-damaging intermediates: role of glycoxidation and oxidative stress in genotoxicity.
Clinically relevant concentrations of two structurally unrelated carboxylic acids, probenecid and clofibric acid, induced DNA damage in isolated hepatocytes via glucuronidation- dependent pathways, suggesting acyl glucuronides are able to access and damage nuclear DNA via iron-catalyzed glycation/glycoxidative processes. Expand
Drug-like properties and the causes of poor solubility and poor permeability.
  • C. Lipinski
  • Chemistry, Medicine
  • Journal of pharmacological and toxicological methods
  • 2000
There are currently about 10000 drug-like compounds, and true diversity does not exist in experimental combinatorial chemistry screening libraries because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Expand
Acyl glucuronides: the good, the bad and the ugly.
A review of the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives concluded that these might be attenuated substantially in vivo by rapid clearance of the conjugates. Expand