400877-57-8Relevant articles and documents
Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure–activity relationship, in vitro and in vivo evaluation as antitumor agents
Islam, Farhana,Quadery, Tasdique M.,Bai, Ruoli,Luckett-Chastain, Lerin R.,Hamel, Ernest,Ihnat, Michael A.,Gangjee, Aleem
supporting information, (2021/04/12)
The design, synthesis, and biological evaluation of a series novel N1?methyl pyrazolo[4,3-d]pyrimidines as inhibitors of tubulin polymerization and colchicine binding were described here. Synthesis of target compounds involved alkylation of the pyrazolo scaffold, which afforded two regioisomers. These were separated, characterized and identified with 1H NMR and NOESY spectroscopy. All compounds, except 10, inhibited [3H]colchicine binding to tubulin, and the potent inhibition was similar to that obtained with CA-4. Compounds 9 and 11–13 strongly inhibited the polymerization of tubulin, with IC50 values of 0.45, 0.42, 0.49 and 0.42 μM, respectively. Compounds 14–16 inhibited the polymerization of tubulin with IC50s near ～1 μM. Compounds 9, 12, 13 and 16 inhibited MCF-7 breast cancer cell lines and circumvented βIII-tubulin mediated cancer cell resistance to taxanes and other MTAs, and compounds 9–17 circumvented Pgp-mediated drug resistance. In the standard NCI testing protocol, compound 9 exhibited excellent potency with low to sub nanomolar GI50 values (≤10 nM) against most tumor cell lines, including several multidrug resistant phenotypes. Compound 9 was significantly (P 0.0001) better than paclitaxel at reducing MCF-7 TUBB3 (βIII-tubulin overexpressing) tumors in a mouse xenograft model. Collectively, these studies support the further preclinical development of the pyrazolo[4,3-d]pyrimidine scaffold as a new generation of tubulin inhibitors and 9 as an anticancer agent with advantages over paclitaxel.
Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity in Vivo
Mugnaini, Claudia,Kostrzewa, Magdalena,Bryk, Marta,Mahmoud, Ali Mokhtar,Brizzi, Antonella,Lamponi, Stefania,Giorgi, Gianluca,Ferlenghi, Francesca,Vacondio, Federica,MacCioni, Paola,Colombo, Giancarlo,Mor, Marco,Starowicz, Katarzyna,Di Marzo, Vincenzo,Ligresti, Alessia,Corelli, Federico
, p. 7369 - 7391 (2020/09/12)
The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
Pyrazolo[4,3-d]pyrimidines as Antitumor Agents
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Paragraph 0048, (2019/09/20)
A compound of Formula I, or optionally a salt or a hydrate of the compound of Formula I is provided: wherein X is one selected from the group consisting of wherein R is an alkyl group having from one to six carbon atoms, and wherein R2 is a halogen atom. A pharmaceutical composition comprising a compound of Formula I, or optionally a salt or a hydrate of the compound of Formula I, and a pharmaceutically acceptable carrier, is provided. A method of treating a patient with cancer is set forth including administering a therapeutically acceptable amount of the compound of Formula I, or a salt or a hydrate of the compound of Formula I, or a pharmaceutical composition comprising a compound of Formula I.
