Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities

The purines: potent and versatile small molecule inhibitors and modulators of key biological targets.

Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer’s disease, asthma, cancer, diabetes, and Parkinson’s disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.

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Caffeine analogs: biomedical impact

3.1.3. Styrylxanthines 248 3.1.4. 9H-Purine derivatives 248 3.2. Pharmacology 248 3.3. Clinical Development and Patents 249 4. A2B Adenosine Receptor Antagonists 250 4.1. Chemistry 250 4.1.1. Xanthines 250 4.1.2. Pyrrolopyrimidines 251 4.2. Pharmacology 252 4.3. Clinical Development and Patents 253 5. A3 Adenosine Receptor Antagonists 253 5.1. Chemistry 254 5.1.1. Xanthines 254 5.1.2. 1,4-Dihydropyridine and Pyridines 255 5.1.3. Pyrazolo-triazolo-pyrimidines 255 5.1.4. Isoquinoline and Quinazoline Urea Analogues as Antagonists for the Human Adenosine A3 Receptor 256

Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility.

Pyrazole scaffold: a remarkable tool in the development of anticancer agents.

In this paper we report the synthesis and biological evaluation of a new class of 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-ones as A3 adenosine receptor antagonists. We designed a new route based on the Kira-Vilsmeier reaction for the synthesis of this class of compounds. Some of the synthesized compounds showed A3 adenosine receptor affinity in the nanomolar range and good selectivity as evaluated in radioligand binding assays at human (h) A1, A2A, A2B, and A3 adenosine receptor subtypes. We introduced several substituents on the 2-phenyl ring. In particular substitution at the 4-position by methyl, methoxy, and chlorine gave optimal activity and selectivity 6c (KihA1, A2A>1000 nM, EC50hA2B>1000 nM, KihA3 = 9 nM), 6d (KihA1, A2A>1000 nM, EC50hA2B>1000 nM, KihA3 = 16 nM), 6b (KihA1, A2A >1000 nM, EC50hA2B>1000 nM, KihA3 = 19 nM). In conclusion, the 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one derivatives described herein represent a new family of in vitro selective antagonists for the adenosin...

New 2-arylpyrazolo[4,3-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists.

Compounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity toward the four adenosine receptors subtypes A1, A2A, A2B, and A3. This paper reports synthesis and biological evaluation of new 1-benzyl-3-propyl-1H,6H-pyrrolo[2,1-f]purine-2,4-diones and 1-benzyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-diones, among which we identified potent and selective A3 adenosine receptors antagonists. In particular, 1-benzyl-7-methyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-dione (11e) shows a Ki (hA3) value from binding assay of 0.8 nM.

Mojgan Aghazadeh Tabrizi

Papers

New 2-arylpyrazolo[4,3-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists.

New Pyrrolo[2,1-f]purine-2,4-dione and Imidazo[2,1-f]purine-2,4-dione Derivatives as Potent and Selective Human A3 Adenosine Receptor Antagonists