Discovery of N-Aryl Piperazines as Selective mGluR₅ Potentiators with Improved In Vivo Utility

Abstract

This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu5 positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu5 chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a ‘molecular switch’. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu5 receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR5 PAM optimized from an HTS-derived mGluR5 competitive antagonist.

Investigating Metabotropic Glutamate Receptor 5 Allosteric Modulator Cooperativity, Affinity, and Agonism: Enriching Structure-Function Studies and Structure-Activity Relationships

“…3 H-labeled 3-methoxy-5-(pyridin-2-ylethynyl)pyridine (methoxy-PEPy) (76.3 Ci/mmol) was custom-synthesized by PerkinElmer Life and Analytical Sciences (Waltham, MA). 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU29), N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), 4-butoxy-N-(2,4-difluorophenyl)benzamide (VU0357121), 2-{4-[2-(benzyloxy)acetyl]piperazin-1-yl}benzonitrile (VU0364289), 1-{[4-(2-phenylethynyl)phenyl]carbonyl}piperidin-4-ol (VU0092273), N-cyclobutyl-6-[(3-fluorophenyl)ethynyl]nicotinamide hydrochloride (VU0360172), 3-fluoro-5-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (VU0285683), 2-(1,3-benzoxazol-2-ylamino)-4-(4-fluorophenyl)pyrimidine-5-carbonitrile (VU0366058), 2-[2- (3-methoxyphenyl) ethynyl]-5-methylpyridine (M-5MPEP), N- were all synthesized in-house by using previously reported methods (Kinney et al, 2005;Rodriguez et al, 2005Rodriguez et al, , 2010Chen et al, 2007Chen et al, , 2008Felts et al, 2010;Hammond et al, 2010;Zhou et al, 2010;Mueller et al, 2012). and N-tertbutyl-6-[2-(3-fluorophenyl)ethynyl]pyridine-3-carboxamide (VU0415051) were synthesized in-house by using the methods described in the supplemental materials.…”

“…2). These compounds represent 11 different chemical scaffolds and a range of allosteric modulator activities, including pure PAMs, PAMs with agonist activity, full NAMs, and weak NAMs (also referred to as partial antagonists or NAMs with low negative cooperativity) (Gasparini et al, 1999;Kinney et al, 2005;Rodriguez et al, 2005Rodriguez et al, , 2010Chen et al, 2007Chen et al, , 2008Felts et al, 2010;Hammond et al, 2010;Zhou et al, 2010;Mueller et al, 2012 (Hammond et al, 2010). However, we used a different cell background and assay conditions (low mGlu 5 expression levels, 1% dimethylsulfoxide, and Ca 2ϩ assay buffer, compared with high mGlu 5 expression levels and a Tris-based buffer) and observed ϳ35% displacement at 30 M. This is consistent with an allosteric interaction between VU0357121.…”

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…Both of these N-aryl piperazine PAMs were also assessed for their ability to modulate glutamate activity of the other seven mGlu subtypes (preliminary data reported for VU0364289 in Zhou et al, 2010). For all subtypes, the potential for modulation of the glutamate concentration response curve was assessed at 10 mM of either PAM, with the exception of mGlu 7 , where L-AP4 was used as the agonist.…”

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

“…Reversal of amphetamine induced hyperlocomotion was readily achieved using VU0364289 (82) at a single dose of 56.6 mg/kg and orderly effects have been observed across multiple doses (unpublished results). 93 Recent i.p. PK studies using VU0364289 (82) indicate rapid and passive CNS penetration (Figure 11).…”