p38 Inhibitors: Piperidine‐ and 4‐Aminopiperidine‐Substituted Naphthyridinones, Quinolinones, and Dihydroquinazolinones.

Hunt, Julianne A.

doi:10.1002/chin.200321139

Cited by 9 publications

(13 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compounds I-III were synthesized and purified at Merck Research Laboratories (Hunt et al, 2002). Microsomes containing individual recombinant human P450 isozymes and monoclonal antibodies against human P450 isozymes were obtained from Drs.…”

Section: Methodsmentioning

confidence: 99%

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR

Yin

Doss²,

Stearns³

et al. 2003

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:We describe herein a novel metabolic fate of the 2,2,6,6-tetramethyl-piperidine (2,2,6,6-TMPi) moiety to a ring-contracted 2,2-dimethyl pyrrolidine (2,2-DMPy) in human liver microsomal incubations. The existence of this pathway was demonstrated for three compounds (I-III) of varied structures suggesting that this may be a general biotransformation reaction for the 2,2,6,6-TMPi moiety. The 2,2-DMPy metabolites formed in incubations of the three compounds with human liver microsomes were characterized by online high performance liquid chromatography coupled to a high resolution hybrid quadrupole-time-of-flight mass spectrometer. Suggested elemental composition obtained from accurate mass measurements of the molecular ions and fragment ions of the metabolites clearly indicated the loss of a mass equivalent to C 3 H 6 from the parent 2,2,6,6-TMPi functionality. Additional accurate tandem mass spectrometry data indicated that one of the original two gem-dimethyl groups was intact in the metabolite structure. Proof of a ring-contracted 2,2-DMPy structure was obtained using 1 H-NMR experiments on a metabolite purified from liver microsomal incubations, which showed only two geminal methyl groups, instead of four in the parent compound. Two-dimensional correlation spectroscopy and decoupling experiments established aliphatic protons arranged in a pyrrolidine ring pattern. The fact that the formation of 2,2-DMPy metabolites in human liver microsomes was NADPH-dependent suggested that this novel metabolic reaction was catalyzed by the cytochrome P450 (P450) enzyme(s). Immunoinhibition studies in human liver microsomal incubations using anti-P450 monoclonal antibodies and experiments with insect cell microsomes containing individually expressed recombinant human P450 isozymes indicated that multiple P450 isozymes were capable of catalyzing this novel metabolic transformation.

show abstract

Section: Methodsmentioning

confidence: 99%

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR

Yin

Doss²,

Stearns³

et al. 2003

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…The same research group has also reported structurally related piperidine-substituted quinolinones, dihydroquinolinones, and naphthyridinones as excellent inhibitors of p38α and TNF-α release, albeit with a comparatively high clearance, only modest oral bioavailability, and low metabolic stability (Table 33) [68].…”

Section: Inhibitors With a Carbonyl Group Attached To A Cyclic Scaffoldmentioning

confidence: 94%

New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase

Peifer¹,

Wagner²,

Laufer³

2006

CTMC

130

View full text Add to dashboard Cite

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.

show abstract

“…For example, structures of the p38 MAP kinase in complex with a variety of inhibitors have been solved and described, and the molecular basis for inhibitor potency and selectivity was well established [80][81][82]. Recently, two new classes of inhibitors have been reported [84][85][86], which showed an increased selectivity for p38 over the closely related MAP kinases ERK and JNK. This unusual specificity could not be explained by simple modeling of the compounds in the p38 ATP-binding site.…”

Section: Use Of Structural Information In Lead Optimizationmentioning

confidence: 98%

Structural Biology and Drug Discovery

Scapin¹

2006

CPD

111

View full text Add to dashboard Cite

In the past few years macromolecular crystallography has become a standard technique used by many pharmaceutical and biotechnology companies. This methodology offers details of protein-ligand interactions at levels of resolution virtually unmatched by any other technique, and this approach holds the promise of novel, more effective, safer and cheaper drugs. Although crystallography remains a laborious and rather expensive technique, remarkable advances in structure determination and structure based drug design (SBDD) have been made in recent years. This process has been aided by recent technological innovations such as high-throughput crystallization, high performance synchrotron beamlines, and new methods in structural bioinformatics and computational chemistry prompted by the structural genomics effort. As a consequence of the increased availability of structural data, the use of structure-based information has expanded from simple protein-ligand interaction analysis to include other aspects of the drug discovery process like target selection and initial lead discovery that used to be almost the exclusive property of biology and chemistry. This review will cover recent examples to illustrate how macromolecular crystallography has evolved and how structural information is now being used in the different stages of the drug discovery process. Advantages and shortcomings of the methodology will also be discussed.

show abstract

p38 Inhibitors: Piperidine‐ and 4‐Aminopiperidine‐Substituted Naphthyridinones, Quinolinones, and Dihydroquinazolinones.

Abstract: Fused pyrimidine derivativesFused pyrimidine derivatives R 0515 p38 Inhibitors: Piperidine-and 4-Aminopiperidine-Substituted Naphthyridinones, Quinolinones, and Dihydroquinazolinones. -(HUNT*, J. A.; et al.; Bioorg.

Cited by 9 publications

References 1 publication

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR

New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase

Structural Biology and Drug Discovery

Contact Info

Product

Resources

About

p38 Inhibitors: Piperidine‐ and 4‐Aminopiperidine‐Substituted Naphthyridinones, Quinolinones, and Dihydroquinazolinones.

Abstract: Fused pyrimidine derivativesFused pyrimidine derivatives R 0515 p38 Inhibitors: Piperidine-and 4-Aminopiperidine-Substituted Naphthyridinones, Quinolinones, and Dihydroquinazolinones. -(HUNT*, J. A.; et al.; Bioorg.

Cited by 9 publications

References 1 publication

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and 1H-NMR

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and 1H-NMR

New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase

Structural Biology and Drug Discovery

Contact Info

Product

Resources

About

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and ¹H-NMR