☆ 4.5 Article

QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A3 receptor subtype

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2011)

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Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 2, Pages 818-823

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.11.094

Keywords

QSAR; Pyrazolotriazolopyrimidines; Adenosine A(3) receptor; GFA; G/PLS

Categories

Chemistry, Medicinal Chemistry, Organic

Funding

  1. CSIR, New Delhi

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Human adenosine A(3) receptor (A(3) AR) binding affinity of pyrazolotriazolopyrimidine derivatives (n = 116) has been subjected to QSAR analyses using three-dimensional (shape, spatial, electronic, and molecular field) along with thermodynamic descriptors to explore the physicochemical requirements for the binding. QSAR models have been validated internally [using leave-one-out cross-validation method] and externally [using test set molecules] to ensure the predictive capacity of the models. The models suggest that shape of the substituent at N-8 position of the pyrazole ring should be optimum. Furthermore, lipophilic substituents having electronegative atoms at NH2 group of C-5 position of the pyrimidine ring with distributed negative charge over the surface may enhance the binding affinity. Again, the carbamoylation of the NH2 group at C-5 position of pyrimidine ring is an essential factor for binding with A(3) receptor. The QSAR models were used for the design and development of some novel thienopyrimidines which were predicted to have good affinity towards A(3) AR. (C) 2010 Elsevier Ltd. All rights reserved.

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