Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines Export

@article{GillespieBBC09, abstract = {doi: 10.1021/jm800961g Antagonism of the human A2A receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A2A receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.}, author = {Gillespie, Roger J. and Bamford, Samantha J. and Botting, Ruth and Comer, Mike and Denny, Sarah and Gaur, Suneel and Griffin, Michael and Jordan, Allan M. and Knight, Anthony R. and Lerpiniere, Joanne and Leonardi, Stefania and Lightowler, Sean and Mcateer, Steven and Merrett, Angela and Misra, Anil and Padfield, Antony and Reece, Mark and Saadi, Mona and Selwood, Daniel L. and Stratton, Gemma C. and Surry, Dominic and Todd, Richard and Tong, Xin and Ruston, Vicki and Upton, Rebecca and Weiss, Scott M.}, citeulike-article-id = {4010417}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/jm800961g}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/jm800961g}, doi = {10.1021/jm800961g}, journal = {Journal of Medicinal Chemistry}, keywords = {a2a, adenosine, antagonist, human, reaction, receptor, subtype}, month = {January}, number = {1}, pages = {33--47}, posted-at = {2009-02-05 08:04:38}, priority = {2}, title = {Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines}, url = {http://dx.doi.org/10.1021/jm800961g}, volume = {52}, year = {2009} }

TY - JOUR ID - GillespieBBC09 L3 - citeulike-article-id:4010417 N2 - doi: 10.1021/jm800961g Antagonism of the human A2A receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson’s disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A2A receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson’s disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec. IS - 1 JF - Journal of Medicinal Chemistry EP - 47 TI - Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines VL - 52 SP - 33 KW - a2a KW - adenosine KW - antagonist KW - human KW - reaction KW - receptor KW - subtype AU - Gillespie, Roger AU - Bamford, Samantha AU - Botting, Ruth AU - Comer, Mike AU - Denny, Sarah AU - Gaur, Suneel AU - Griffin, Michael AU - Jordan, Allan AU - Knight, Anthony AU - Lerpiniere, Joanne AU - Leonardi, Stefania AU - Lightowler, Sean AU - Mcateer, Steven AU - Merrett, Angela AU - Misra, Anil AU - Padfield, Antony AU - Reece, Mark AU - Saadi, Mona AU - Selwood, Daniel AU - Stratton, Gemma AU - Surry, Dominic AU - Todd, Richard AU - Tong, Xin AU - Ruston, Vicki AU - Upton, Rebecca AU - Weiss, Scott PY - 2009/01// UR - http://dx.doi.org/10.1021/jm800961g ER -