Jung Juyoung, Lee Yoonsuk, Moon An-Na, Ann Jihyae, Jeong Jin Ju, Do Nayeon, Lee Jeewoo
iLeadBMS Co., Ltd., Hwaseong-si 18469, Korea.
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
Pharmaceuticals (Basel). 2022 Jul 25;15(8):922. doi: 10.3390/ph15080922.
New compounds with 1-pyrazolo [3,4]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A and A receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, showed high binding activities (A K = 13.3 nM; A K = 55 nM) and full antagonism (A IC = 136 nM; A IC = 98.8 nM) toward both receptors. Further tests showed that has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 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, tended to improve behavior. Moreover, dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A/A receptor antagonist, , is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.
合成了具有1-吡唑并[3,4]嘧啶-6-胺核心骨架的新型化合物，并在体外对其进行了表征，以确定它们对人A和A受体的亲和力。在测试的化合物中，有几种化合物对这两种受体都表现出纳摩尔级的结合亲和力。一种特定的化合物，对两种受体都表现出高结合活性（A K = 13.3 nM；A K = 55 nM）和完全拮抗作用（A IC = 136 nM；A IC = 98.8 nM）。进一步的测试表明，在小鼠中具有低肝清除率和良好的药代动力学特性，以及高生物利用度和高脑血浆比率。此外，与极低的心血管风险和致突变潜力相关，并且在大鼠和狗中耐受性良好。在MPTP诱导的帕金森病小鼠模型中进行测试时，倾向于改善行为。此外，在雌性大鼠中剂量依赖性地逆转氟哌啶醇诱导的僵住症，分级ED在3至10 mg/kg之间。综上所述，这些结果表明，这种强效的双重A/A受体拮抗剂是治疗帕金森病的良好候选药物，具有优异的代谢和安全性。
