Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson’s Disease Agents

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2022-07, Vol.15 (8), p.922
• Main Authors: Jung, Juyoung, Lee, Yoonsuk, Moon, An-Na, Ann, Jihyae, Jeong, Jin Ju, Do, Nayeon, Lee, Jeewoo
• Format: Article
• Language: English
• Subjects: Adenosine; adenosine receptor antagonist; animal model; Dopamine; Hypotheses; Parkinson's disease; pharmacokinetic
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15080922

New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A2A and A1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA2A Ki = 13.3 nM; hA1 Ki = 55 nM) and full antagonism (hA2A IC50 = 136 nM; hA1 IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson’s disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A2A/A1 receptor antagonist, 11o, is a good candidate for the treatment of Parkinson’s disease with an excellent metabolic and safety profile.