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10.1021/ml3003007 http://scihub22266oqcxt.onion/10.1021/ml3003007 C4027423!4027423!24900567     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24900567&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       ACS+Med+Chem+Lett 2013 ; 4 (1): 85-90 Nephropedia Template TP {{tp|p=24900567|t=2013. Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor |pdf=|usr=}}{{24900567}} gab.com Text Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor JO: ACS Med Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=24900567 #FOAvip The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs. Twit Text FOAVip Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor ????ACS Med Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=24900567 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24900567 #FOAvip English Wikipedia <ref>{{Cite pmid|24900567}}</ref> Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor #MMPMID24900567 Chan BK; Estrada AA; Chen H; Atherall J; Baker-Glenn C; Beresford A; Burdick DJ; Chambers M; Dominguez SL; Drummond J; Gill A; Kleinheinz T; Le Pichon CE; Medhurst AD; Liu X; Moffat J; Nash K; Scearce-Levie K; Sheng Z; Shore D; Van de Poël H; Zhang S; Zhu H; Sweeney Z ACS Med Chem Lett 2013[Jan]; 4 (1): 85-90 PMID24900567show ga The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs. äDiscovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 I(epmc).pdf DeepDyve Pubget Overpricing