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

Juyoung Jung; Yoonsuk Lee; An-Na Moon; Jihyae Ann; Jin Ju Jeong; Nayeon Do; Jeewoo Lee

doi:10.3390/ph15080922

Discovery of Novel Dual Adenosine A_2A and A₁ Receptor Antagonists with 1 H-Pyrazolo[3,4 -d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents

Pharmaceuticals (Basel). 2022 Jul 25;15(8):922. doi: 10.3390/ph15080922.

Authors

Juyoung Jung¹, Yoonsuk Lee¹, An-Na Moon¹, Jihyae Ann², Jin Ju Jeong², Nayeon Do², Jeewoo Lee²

Affiliations

¹ iLeadBMS Co., Ltd., Hwaseong-si 18469, Korea.
² Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Abstract

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 A_2A 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 (hA_2A K_i = 13.3 nM; hA₁ K_i = 55 nM) and full antagonism (hA_2A 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 A_2A/A₁ receptor antagonist, 11o, is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.

Keywords: Parkinson’s disease; adenosine receptor antagonist; animal model; pharmacokinetic.

Grants and funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021).