Discovery of 2‐(2‐Benzoxazoyl amino)‐4‐Aryl‐5‐Cyanopyrimidine as Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptor 5 (mGlu₅): From an Artificial Neural Network Virtual Screen to an In Vivo Tool Compound

Abstract

From ANNs to NAMs! Data from an experimental metabotropic glutamate receptor 5 (mGlu5) high‐throughput screen (HTS) were employed to train artificial neural networks (ANNs) based on 345 confirmed negative allosteric modulators (NAMs) and 155 774 inactive compounds. This effort identified two potent mGlu5 NAMs with a unique chemotype. Optimization afforded a tool compound (shown), active in mouse models of anxiety and addiction.

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

“…1C). In contrast, the potencies of mGlu 5 PAMs were often higher than their estimated affinities at the prototypical allosteric site labeled with Poon et al, 2004;Roppe et al, 2004;Chua et al, 2005;Tehrani et al, 2005;de Paulis et al, 2006;Kulkarni et al, 2006Kulkarni et al, , 2009Jaeschke et al, 2007;Milbank et al, 2007;Liu et al, 2008;Vanejevs et al, 2008;Felts et al, 2009Felts et al, , 2010Galambos et al, 2010;Rodriguez et al, 2010;Wágner et al, 2010;Zhang et al, 2010;Alagille et al, 2011;Gilbert et al, 2011;Lindemann et al, 2011;Sams et al, 2011;Weiss et al, 2011;Zou et al, 2011;Mueller et al, 2012). Dashed lines, unity; dotted lines, potency and affinity within 3-fold of each other; solid lines, 10-fold difference.…”

“…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.…”

Computational Methods in Drug Discovery

“…This hit rate of 28.2% was approximately 30 times greater than that of the original HTS, and the virtual screen took approximately 1 hour to complete once the model had been optimized (Fig. 16) (Mueller et al, 2012).…”

“…This presents a more potent inhibition of tyrosinase than the current reference Computational Methods in Drug Discovery drug L-mimosine (IC 50 = 3.68 mM) (Casañola- Martin et al, 2007). Mueller et al (2012) used ANN QSAR models to identify novel positive and negative allosteric modulators of mGlu5. This receptor has been implicated in neurologic disorders including anxiety, Parkinson's disease, and schizophrenia (Gasparini et al, 2008;Conn et al, 2009).…”

“…QSAR-based virtual screening of mGlu5 negative allosteric modulators yields lead compounds that contain substructure combinations taken across several known actives used for model generation. Adapted from Mueller et al (2012). known kinase inhibitors. Potential scaffold fragments were identified using substructure and similarity searching, and break points for fragment generation were guided with structure-based pharmacophores.…”