Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.

Autor:	McAllister LA; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Butler CR; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Mente S; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., O'Neil SV; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Fonseca KR; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Piro JR; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Cianfrogna JA; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Foley TL; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Gilbert AM; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Harris AR; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Helal CJ; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Johnson DS; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Montgomery JI; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Nason DM; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Noell S; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Pandit J; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Rogers BN; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Samad TA; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Shaffer CL; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., da Silva RG; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Uccello DP; Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States., Webb D; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States., Brodney MA; Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Apr 12; Vol. 61 (7), pp. 3008-3026. Date of Electronic Publication: 2018 Mar 15.
DOI:	10.1021/acs.jmedchem.8b00070
Abstrakt:	Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log  D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
Databáze:	MEDLINE
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