163042-96-4Relevant articles and documents
Design and in vivo activity of A3 adenosine receptor agonist prodrugs
Suresh, R. Rama,Jain, Shanu,Chen, Zhoumou,Tosh, Dilip K.,Ma, Yanling,Podszun, Maren C.,Rotman, Yaron,Salvemini, Daniela,Jacobson, Kenneth A.
, p. 367 - 377 (2020/07/31)
Prodrugs (MRS7422, MRS7476) of highly selective A3 adenosine receptor (AR) agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3?μmol/kg, p.o.), a known A3AR effect. MRS7476 (5?mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation.?Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR agonists in models of two disease conditions.
Purine nucleosides
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Page/Page column Sheet 1 of 3, (2010/02/14)
Disclosed are purine nucleoside compounds that are selective to A3 adenosine receptors and are useful for the treatment of cancer and inflammatory diseases. The compounds are shown by the following general formula (I), including isomers thereof: wherein X is sulfur or oxygen; R1 is hydrogen, alkyl, benzyl, halobenzyl, or phenylalkyl; R2 is hydrogen, halogen, alkoxy, alkenyl, alkynyl, alkylthio, or thio; R3 and R3′ are hydrogen, hydroxyalkyl, alkoxycarbonyl, or alkylaminocabonyl, whereas R3 and R3′ do not have identical substituents simultaneously; and R4 is hydrogen or alkyl. Also disclosed are a pharmaceutical composition comprising a compound of formula (I), an isomer, or its pharmacologically acceptable salt as an active ingredient and a method for preventing or treating various diseases, state, or condition, including asthma, inflammation, cerebral ischemia, heart diseases, and cancer.