Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators

Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of an mGluR4 positive allosteric modulator lead based on a pyrazolo[3,4-d]pyrimidine scaffold. Despite tremendous therapeutic potential, Compound 7, VU0080421, and related congeners represent only a handful of mGluR4 positive allosteric modulators ever described.

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

“…More recently, a series of papers have described useful advances based on several different chemical scaffolds. This jpet.aspetjournals.org includes molecules with improved selectivity for mGluR4 (Niswender et al, 2008b;Williams et al, 2010) and improved central nervous system penetration (Williams et al, 2009(Williams et al, , 2010East and Gerlach, 2010). This approach has also recently generated mGluR4 receptor antagonists (Utley et al, 2011).…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…Nevertheless, VU0155041, which also has some partial agonist activity, represents an improvement over PHCCC in terms of aqueous solubility and selectivity for the mGlu4 receptor. Subsequent HTS efforts then yielded novel structures of positive mGlu4 receptor modulators (Table 9, III-V) (Niswender et al, 2008b;Williams et al, 2009b), but little or no tractable SAR were again encountered. In a series of heterobiarylamides, some compounds with submicromolar potency and relatively good central penetration were found (Engers et al, 2009a).…”

Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications

“…In in vitro mGlu 4 assays, PHCCC exhibits no agonist activity by itself but increases the potency of glutamate at mGlu 4 and acts as a proof-of-concept compound for targeting mGlu 4 as a potential therapeutic strategy for disorders such as Parkinson's disease (Marino, Williams et al 2003). Further optimization of the PHCCC scaffold has been challenging (Niswender et al, 2008, Williams et al 2010); however, a high-throughput screening campaign led to the identification of VU0155041 and VU0080421 as examples of non-PHCCC scaffold mGlu 4 PAMs (Niswender, Johnson et al 2008, Niswender, Lebois et al 2008). Recently, many other mGlu 4 PAMs, including 4PAM-2, VU0364770, ADX88178, LuAF21934 and others (Drolet, Tugusheva et al 2011, Jones, Bubser et al 2012, Le Poul, Bolea et al 2012, Bennouar, Uberti et al 2013), have emerged with significant improvements in potency, selectivity and pharmacokinetic profile compared to PHCCC.…”