title: Optimization of 6-heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)pyrimidin-4-amine as potent adenosine A2A receptor antagonists for the treatment of Parkinson's disease.
abstract: Parkinson's disease is a neurodegenerative disease characterized by the motor symptoms of bradykinesia, tremor, and rigidity. Current therapies are based mainly on dopaminergic replacement strategies by administration of either dopamine agonists or dopamine precursor levodopa (L-Dopa). These treatments provide symptomatic relief without slowing or stopping the disease progression, and long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinisia. Unfortunately, there had been few novel treatments developed in the past decades. Among nondopaminergic strategies for the treatment of Parkinson's disease, antagonism of the adenosine A2A receptor has emerged to show great potential. Here we report the optimization of a new chemical scaffold, which achieved exceptional receptor binding affinity and ligand efficiency against adenosine A2A receptor. The leading compounds demonstrated excellent efficacy in the haloperidol induced catalepsy model for Parkinson's disease.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Su Zhou, Jiangsu 215021, P. R. China.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zheng
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.forename: Linlang
authors.initials: L
authors.lastname: Li
authors.forename: Haikuo
authors.initials: H
authors.lastname: Ma
authors.forename: Meiyu
authors.initials: M
authors.lastname: Wang
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D002375:Catalepsy; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057809:HEK293 Cells; D006220:Haloperidol; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011743:Pyrimidines / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism
chemical_list: C547768:ADRA2A protein, human; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011743:Pyrimidines; D018341:Receptors, Adrenergic, alpha-2; D006220:Haloperidol