Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

Abstract

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of nonamide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one 11, VU0462054), bearing a simple ketone moiety, was identified (LE = 0.52, LELP = 3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

“…These mutagenesis studies pointed to a common location for allosteric binding pockets for group I mGlu receptors. Additional studies have shown that residues at positions 3.40 and 7.38 are important for allosteric modulation of both mGlu 1 and mGlu 5 [Ballesteros-Weinstein numbering (Ballesteros and Weinstein, 1995) adopted from mGlu 1 structural alignment to family A GPCRs; Malherbe et al, 2003aMalherbe et al, ,b, 2006Muhlemann et al, 2006;Suzuki et al, 2007;Fukuda et al, 2009;Gregory et al, 2012Gregory et al, , 2013bGregory et al, , 2014Turlington et al, 2014;Wu et al, 2014]. Subsequently, key residues for the potency and/or binding of mGlu 1 , mGlu 2 , mGlu 4 , and mGlu 5 allosteric modulators from diverse chemical scaffolds have been mapped to TMs 3-7.…”

“…Across the four subtypes multiple residues have repeatedly been reported as contributing to allosteric modulation. For all four subtypes, residues in positions 3.36, 5.43, and 6.48 are crucial for both positive and negative allosteric modulators (Pagano et al, 2000;Malherbe et al, 2003aMalherbe et al, , 2006Muhlemann et al, 2006;Fukuda et al, 2009;Lundstrom et al, 2011;Gregory et al, 2012Gregory et al, , 2013bGregory et al, , 2014Molck et al, 2012;Turlington et al, 2014;Wu et al, 2014;Rovira et al, 2015). Position 7.45 has also been implicated in mGlu 4 and mGlu 5 allosteric modulation (Molck et al, 2012;Gregory et al, 2013bGregory et al, , 2014Turlington et al, 2014;Rovira et al, 2015); there are no reports investigating the influence of this amino acid on selective allosteric modulators of mGlu 1 or mGlu 2 .…”

“…For all four subtypes, residues in positions 3.36, 5.43, and 6.48 are crucial for both positive and negative allosteric modulators (Pagano et al, 2000;Malherbe et al, 2003aMalherbe et al, , 2006Muhlemann et al, 2006;Fukuda et al, 2009;Lundstrom et al, 2011;Gregory et al, 2012Gregory et al, , 2013bGregory et al, , 2014Molck et al, 2012;Turlington et al, 2014;Wu et al, 2014;Rovira et al, 2015). Position 7.45 has also been implicated in mGlu 4 and mGlu 5 allosteric modulation (Molck et al, 2012;Gregory et al, 2013bGregory et al, , 2014Turlington et al, 2014;Rovira et al, 2015); there are no reports investigating the influence of this amino acid on selective allosteric modulators of mGlu 1 or mGlu 2 . Between group I mGlu receptors and mGlu 2 , three residues are common: 5.44, 5.47, and 6.55 (Knoflach et al, 2001;Malherbe et al, 2003bMalherbe et al, , 2006Schaffhauser et al, 2003;Hemstapat et al, 2006;Muhlemann et al, 2006;Rowe et al, 2008;Fukuda et al, 2009;Lundstrom et al, 2011;Gregory et al, 2012Gregory et al, , 2013bGregory et al, , 2014Molck et al, 2012).…”

“…Grayscale: white, 3-to 10-fold change; light gray, 10-to 30-fold change; mid gray, 30-to 100-fold decrease; dark gray, .100-fold decrease or complete loss of radiolabeled allosteric modulator binding (data summarized from: Pagano et al, 2000;Malherbe et al, 2003aMalherbe et al, ,b, 2006Gregory et al, 2012Gregory et al, , 2013bGregory et al, , 2014Turlington et al, 2014;Wu et al, 2014).…”

“…Substitution of Y6.51 at mGlu 5 switches DFB from a PAM of glutamate to a NAM, whereas the reverse is true for YM298198 at mGlu 1 (Muhlemann et al, 2006;Fukuda et al, 2009). Multiple additional point mutations in TMs 3, 6, and 7 can also switch acetylenic PAMs to have either neutral or negative cooperativity with glutamate at mGlu 5 (Gregory et al, 2013b;Turlington et al, 2014). Mutation of conserved W785 6.48 in mGlu 5 can switch the cooperativity of select NAMs of glutamate to positive .…”