Synthesis and evaluation of 1,2,4-triazolo[1,5-c]pyrimidine derivatives as A2A receptor-selective antagonists

Abstract

Movement disorders such as Parkinson's disease and Huntington's disease are serious life-limiting and debilitating movement disorders. Their onset typically occurs from mid-life to late in life, and effective diagnostic techniques for detecting and following the disease course are lacking. Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectively target the most relevant subtype of adenosine receptors (AR) that are highly expressed in the striatum, i.e. the A 2A AR. To further this goal, we have synthesized and characterized pharmacologically a family of high affinity A 2A AR ligands, based on the known antagonist, SCH 442416 (R = -Me), which have structural variability on the terminus (R = -Et, -i-Pr, -allyl, and others). A O-fluoroethyl analogue suitable for use as a PET tracer had a K i value of 12.4 nM and was highly selective for the A 2A AR in comparison to the A 1 and A 3 ARs. Keywordsnucleoside; G protein-coupled receptor; molecular modelling; adenosine receptor; radioligand binding Movement disorders such as Parkinson's disease (PD) and Huntington's disease (HD) are serious life-limiting and debilitating movement disorders affecting roughly 1% of the the U.S. population over age 50 [1,2]. The onset of these neurodegenerative diseases typically occurs from mid-life to late in life. By the time a diagnosis is made, damage to the neuronal pathways in the brain governing movement is well-advanced. One problem is a lack of adequate diagnostic techniques for detecting and following the course of these diseases. This clearly holds true for Parkinkson's disease for which there currently is no predictive genetic test. Even with respect to Huntington's disease, which is entirely of a genetic origin, there remains a need Corresponding author: Dr. W. C. Trenkle, Chemical Biology Unit, Bldg. 8, Rm. 121, NIH, NIDDK, LCBB, Bethesda, MD 20892-0810. Tel: 301-402-2699. Fax: 301-402-2639; wtrenkle@niddk.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary dataSupplementary data (chemical synthesis, characterization data, additional pharmacological procedures, and additional modeling information) associated with this article can be found, in the online version, at doi:. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2011 October 1. for new tools to follow the progress of the neurodegeneration and to assess the effectiveness of experimental drugs by objective criteria.Our goal is to develop receptor imaging agents for positron emission tomography (PET) that selectivel...

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“…In vitro metabolism evaluation was conducted in cryopreserved rat hepatocytes with analysis of the generated metabolites by HPLC-MS [32]. Authentic non-radioactive MRS5425 (7-(3-(4-(2-fluoroethoxy)phenyl)propyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine), was prepared as previously described [33]. …”

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“…Values are expressed as the mean ± SEM. ND, not determined. b Data from Shinkre et al [14] and Kecskes et al [19]. …”

“…the A 2A AR, we developed a O -(3-fluoropropyl) analogue, intended for incorporation of 18 F. It was essential to identify an insensitive position on 2 that would accommodate a chain. The methoxy group of the phenyl ring of 2 was selected for this purpose because it has been shown to display flexibility of substitution and conformation with respect to binding to the A 2A AR, as deduced from structure activity relationship (SAR) studies in conjunction with molecular modeling and ligand docking [14]. …”

“…Shinkre et al reported the removal of the methyl ether of 2 as a means of further derivatizing this series of A 2A AR antagonists [14]. Commercially available SCH 442416 was demethylated using BBr 3 in CH 2 Cl 2 to yield phenol 3 , which was used in the next reaction without further purification.…”