pyrimidinones and Arthritis

Topics: Analgesics; Arthritis; Arthritis, Rheumatoid; Chemical Phenomena; Chemistry; Drug Therapy, Combination; Drug Tolerance; Gastrointestinal Hemorrhage; Humans; Indomethacin; Pain; Pyrimidinones

A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.

Topics: Administration, Oral; Animals; Arthritis; Arthritis, Experimental; Caco-2 Cells; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Male; Models, Molecular; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyrimidinones; Rats; Rats, Inbred Lew; Structure-Activity Relationship

Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Benzimidazoles; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Enzyme Activation; Female; Injections, Intradermal; Interleukin-2; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Male; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrimidinones; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Reproducibility of Results; Stereoisomerism; Structure-Activity Relationship; T-Lymphocytes

In an extensive analysis of the antiviral and interferon-induction structure-activity relationship of 6-arylpyrimidinones we found that modifications at positions 1-4 of the pyrimidine ring resulted in a loss of activity. However, we uncovered interesting hypotensive and antiinflammatory activity with a series of N-substituted analogues, the results of which we report herein.

Topics: Animals; Anti-Inflammatory Agents; Antiviral Agents; Arthritis; Diuresis; Dose-Response Relationship, Drug; Female; Furosemide; Guanethidine; Heart; Hydrochlorothiazide; Hypotension; Male; Methylation; Natriuresis; Phenylacetates; Potassium; Pyrimidinones; Rats; Rats, Inbred Strains; Stilbenes; Structure-Activity Relationship; Tamoxifen