title: Identification of a New Series of Potent Adenosine A2AReceptor Antagonists Based on 4-Amino-5-carbonitrile Pyrimidine Template for the Treatment of Parkinson's Disease.
abstract: Adenosine receptor A2Aantagonists have emerged as potential treatment for Parkinson's disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2Aantagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson's disease.
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Zhaohui
authors: Z
authors: Yang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Linlang
authors: L
authors: Li
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Jiyue
authors: J
authors: Zheng
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Haikuo
authors: H
authors: Ma
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Sheng
authors: S
authors: Tian
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Jiajun
authors: J
authors: Li
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Hongjian
authors: H
authors: Zhang
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Xuechu
authors: X
authors: Zhen
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors: Xiaohu
authors: X
authors: Zhang
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006220:Haloperidol; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011743:Pyrimidines; D006220:Haloperidol
keywords: Adenosine receptor; GPCR; Parkinson’s disease; antagonist; lead identification