Pyrazolo-pyrimidines: A novel heterocyclic scaffold for potent and selective p38α inhibitors
Graphical abstract
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2x was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38α is also disclosed.
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2023, Polycyclic Aromatic CompoundsSynthesis, evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory, ulcerogenic and TNF-α inhibitory properties
2019, Bioorganic ChemistryCitation Excerpt :Literature survey on pyrazolo[3,4-d]pyrimidines has shown that these derivatives also possess good p38α MAP kinase inhibition [23–26] (Fig. 1). Encouraged by these observations and in continuation of our ongoing research program [26–32] to discover new and improved anti-inflammatory agents, we report herein the synthesis and pharmacological evaluation of pyrazolo[3,4-d]pyrimidine derivatives as potential anti-inflammatory agents. Nine pyrazolo [3,4-d] pyrimidine derivatives were synthesized by following the procedure mentioned under Scheme 1.
Anti-inflammatory drug approach: Synthesis and biological evaluation of novel pyrazolo[3,4-d]pyrimidine compounds
2019, Bioorganic ChemistryCitation Excerpt :Several compounds as xanthene attached amino acids [15], piperazine-1-carbothioamide chitosan silver nanoparticles [16], dihydrazones [17], coumarins [18], benzo[d]thiazoles [19] and sulfur containing motifs [20] have exhibited anti-inflammatory activities. The anti-inflammatory properties of pyrazolo[3,4-d]pyrimidine compounds as potential inhibitors of cyclooxygenase (COX) [21] and p38α isoenzymes [22,23] are well known and gaining more interest. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly prescribed medications to alleviate acute and chronic inflammation, pain and fever.
Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidines as anti-inflammatory agents
2018, Bioorganic ChemistryCitation Excerpt :Therefore, development of novel compounds having anti-inflammatory activity with an improved gastrointestinal safety profile is a necessity. Pyrazolo[3,4-d]pyrimidines either linked to or fused with other heterocyclic ring systems constitute an important scaffold in several pharmacologically active compounds including anti-inflammatory [11–16], and analgesic agents [17–20]. Literature survey revealed that DPP; (N4-benzyl-1-(tert-butyl)-N6,N6-dimethyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine) (A, Fig. 1) possess anti-inflammatory and analgesic activities in addition to higher selectivity for COX-2 over COX-1 [21].
Design, synthesis and pharmacological evaluation of some pyrazolopyrimidin-6(7H)-ones and tricyclic 8-oxo-dihydrooxazolopyrazolopyrimidin-9-ium chloride derivatives
2017, Arabian Journal of ChemistryCitation Excerpt :Additionally, Alagarsamy et al. (2006) synthesized and evaluated a series of fused tricyclic compounds having tetrahydrobenzothienopyrimidine nucleus and few of them exhibited potent anti-inflammatory activity with better ulcer index. Das et al. (2008b) suggest that the pyrazolopyrimidine scaffold elicits their anti-inflammatory activities via selective inhibition of mitogen activated protein kinase p38α. Activation of p38α leads to upregulation of pro-inflammatory cytokines such as TNFα and IL-1β.