Discovery of VU6005649, a CNS Penetrant mGlu 7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5- a ]pyrimidines.

Autor: Abe M; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Seto M; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Gogliotti RG; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Loch MT; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Bollinger KA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Chang S; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Engelberg EM; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Luscombe VB; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Harp JM; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Bubser M; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Engers DW; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Jones CK; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States., Rodriguez AL; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Blobaum AL; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States., Conn PJ; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States., Niswender CM; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States., Lindsley CW; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2017 Sep 01; Vol. 8 (10), pp. 1110-1115. Date of Electronic Publication: 2017 Sep 01 (Print Publication: 2017).
DOI: 10.1021/acsmedchemlett.7b00317
Abstrakt: Herein, we report the structure-activity relationships within a series of mGlu 7 PAMs based on a pyrazolo[1,5- a ]pyrimidine core with excellent CNS penetration ( K p s > 1 and K p,uu s > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu 7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.
Databáze: MEDLINE
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