Pyrroles and other heterocycles as inhibitors of P38 kinase (original) (raw)
Related papers
TNF-α and IL-1β inhibitors, 3, 5-disubstituted-4, 5-dihydro-1H-pyrazoles
Biomedical Research-tokyo, 2017
A series of 3, 5-disubstituted-4, 5-dihydro-1H-pyrazoles have been synthesized under solvent free microwave irradiation method by the condensation of α, β-unsaturated ketones with hydrazine and its differently substituted derivatives. The chemical structures of the compounds were characterized by elemental analysis and spectroscopic data. All the synthetics were evaluated for their anti-inflammatory activity under in vivo conditions. The present study describes the potential of these pyrazole ring containing scaffolds to assess the TNF α (Tumor Necrosis Factor-alpha) and IL-1β (Interleukin-1 beta) inhibitory potential. TNF-α and IL-1β are inflammatory cytokines that are pro-inflammatory in nature and play a major role in inflammatory cascades of many pathologically dreadful diseases ranging from neurodegenerative disorders to autoimmune diseases such as rheumatoid arthritis.
SAR of 2,6-diamino-3,5-difluoropyridinyl substituted heterocycles as novel p38MAP kinase inhibitors
Bioorganic & Medicinal Chemistry Letters, 2002
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38a inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFa in mice, showed good efficacy in the established rat adjuvant (ED 50 : 10 mg/kg po b.i.d.) and collagen induced arthritis (ED 50 : 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints. #
Bioorganic & Medicinal Chemistry Letters, 2009
Two series of nitrogenous heterocycle compounds-1,2,4-trisubstituted imidazoles and 1,3,5-trisubstituted pyrazoles have been synthesized and evaluated for their ALK5 inhibitory activity and cytotoxicity in TGFb-Smad2 assay and MTT assay, respectively. The ALK4/5/7 inhibitory activity of some compound was also evaluated in ALK4/5/7 autophosphorylation assays. Compounds 6c and 14c showed relatively potent ALK5 inhibition while weak cytotoxicity. At the same time, compounds 6c and 14c display relatively better ALK5 selectivity versus ALK4/ALK7 (nearly 10-fold) compared with SB431542, a well known ALK5 inhibitor. Compound 6g2 proved to be a moderately selective ALK4 inhibitor versus ALK5 and ALK7 (>10-fold). The binding mode of 14c generated by flexible docking study shows that 14c fits well into the site cavity of ALK5 by forming several tight interactions.
Design, synthesis and pharmacological assessment of new pyrazole compounds
Inflammopharmacology, 2020
Aims This study investigated the antinociceptive and anti-inflammatory effects of new pyrazole compounds LQFM011(5), LQFM043(6) and LQFM044(7) as well as the mechanisms of action and acute in vitro toxicity. Main methods The antinociceptive activity was evaluated using the acetic acid-induced abdominal writhing test, formalininduced pain test and the Randall-Selitto test. The anti-inflammatory activity was evaluated using models of paw oedema and pleurisy induced by carrageenan; cell migration, the levels of tumour necrosis factor α (TNF-α) and myeloperoxidase (MPO) enzyme activity were evaluated. In addition, the ability to inhibit phospholipase A2 (PLA2) in vitro and docking in PLA2 were used. Acute oral systemic toxicity in mice was evaluated through the neutral red uptake assay. Key findings The synthesised compounds (5-7), delivered via gavage (p.o.) at 70, 140 or 280 µmol/kg, decreased the number of writhings induced by acetic acid; the three compounds (280 µmol/kg p.o.) reduced the paw licking time in the first and second phase of the formalin test and decreased the nociceptive threshold variation in the Randall-Selitto test. Furthermore, this dose reduced oedema formation, leucocyte migration (specifically through reduction in polymorphonuclear cell movement) and increased mononuclear cells. MPO activity and the levels of pro-inflammatory cytokines TNF-α were decreased. Evaluation of PLA2 inhibition via the docking simulation revealed more interactions of LQFM043R(6) and LQFM044(7), data that corroborated the half-maximal inhibitory concentration (IC 50) of PLA2 inhibition in vitro. Therefore, LQFM011(5), LQFM043(6) and LQFM044(7) were classified with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as category 4.
Bioorganic & Medicinal Chemistry Letters, 2009
A novel class of fused pyrazole-derived inhibitors of p38a mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNFa in a LPS-challenged THP1 cell line and TNFa-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC 50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED 50 of 0.1 mg/kg while 10q was found to have an ED 50 of 0.05-0.07 mg/kg.
Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X 7 antagonists
Bioorganic & Medicinal Chemistry Letters, 2010
A series of analogues of the pyrazole lead 1 were synthesized in which the heterocyclic core was replaced with an imidazole. A number of potent antagonists were identified and structure-activity relationships (SAR) were investigated both with respect to activity at the P2X 7 receptor and in vitro metabolic stability. Compound 10 was identified as a potent P2X 7 antagonist with reduced in vitro metabolism and high solubility.