Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu₇ Positive Allosteric Modulator Tool Compound

Abstract

Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a “molecular switch” within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1

“…Allosteric modulators of glutamate receptors have been shown to exhibit steep SAR profiles, as exemplified by the effect of replacing the ester moiety of the modestly potent mGlu 7 negative allosteric modulator (NAM) 97 with a nitrile to give 98 (Figure ). − The nitrile 98 exhibits an inverted profile at the mGlu 7 receptor compared to 97 , acting as a positive allosteric modulator (PAM) that, although a potentially useful tool molecule, was associated with dopamine transporter (DAT) inhibition . As part of the effort to resolve the DAT liability of 98 , a survey of potential replacements for the piperazine scaffold was conducted (Figure ).…”

“…71−73 The nitrile 98 exhibits an inverted profile at the mGlu 7 receptor compared to 97, acting as a positive allosteric modulator (PAM) that, although a potentially useful tool molecule, was associated with dopamine transporter (DAT) inhibition. 73 As part of the effort to resolve the DAT liability of 98, a survey of potential replacements for the piperazine scaffold was conducted (Figure 12). However, as is evident from the data compiled in Figure 12, even conservative changes to this heterocycle produced only inactive compounds, reinforcing the high sensitivity of receptor recognition to small changes in structure.…”

Differential activity of mGlu7 allosteric modulators provides evidence for mGlu7/8 heterodimers at hippocampal Schaffer collateral-CA1 synapses

“…Calcium assays in which rat mGlu 7 was coupled to calcium mobilization via the promiscuous G protein G α15 were used to determine in vitro potency and efficacy and were conducted as described in ( 18 , 26 , 41 , 42 , 43 ).…”

Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu7 Receptor Modulation Activity and Antipsychotic-Like Properties

“…Recent discoveries of potent, highly selective, orally bioavailable, CNS penetrant, and metabolically stable NAM and PAM mGlu7 modulators, VU6019278 [37] and VU6027459 [40], respectively, as shown in Figure 2, have provided new opportunities for essential research on mGlu7 receptor pharmacology. [13,17,18,20,21,29,36,38,39].…”