Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1.
Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Jason T
JT
Manka
Alice L
AL
Rodriguez
Ryan D
RD
Morrison
Daryl F
DF
Venable
Hyekyung P
HP
Cho
Anna L
AL
Blobaum
J Scott
JS
Daniels
Colleen M
CM
Niswender
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
Kyle A
KA
Emmitte
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011758:Pyrroles; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C587365:octahydropyrrolo(3,4-c)pyrrole; D003577:Cytochrome P-450 Enzyme System
Allosteric modulator; CNS; GPCR; Glutamate; Octahydropyrrolo[3,4-c]pyrrole; mGlu(1)