2019
DOI: 10.1016/j.bmcl.2018.10.050
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The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate

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Cited by 7 publications
(6 citation statements)
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“…Several derivatives were discovered to be inactive or exhibited a loss of activity. The optimization campaign led to compounds 41 and 42 (Figure ), which showed resolved issues of CYP1A2 induction, and 41 was inactive against all CYP enzymes studied (CYP1A2, 3A4, 2C9, 2D6: >30 μM). ,, In addition, 41 was evaluated in mGluR selectivity panel, and it was inactive against all the other mGluR subtypes (mGluR6 was not included). The author noted that while these potent derivatives also showed some solubility issues, which could hinder their application in drug development, they may not pose a significant obstacle for PET tracer development given the microdosing approach used in nuclear medicine.…”
Section: Chemotypes and Available Radioligands For Mglur4mentioning
confidence: 99%
“…Several derivatives were discovered to be inactive or exhibited a loss of activity. The optimization campaign led to compounds 41 and 42 (Figure ), which showed resolved issues of CYP1A2 induction, and 41 was inactive against all CYP enzymes studied (CYP1A2, 3A4, 2C9, 2D6: >30 μM). ,, In addition, 41 was evaluated in mGluR selectivity panel, and it was inactive against all the other mGluR subtypes (mGluR6 was not included). The author noted that while these potent derivatives also showed some solubility issues, which could hinder their application in drug development, they may not pose a significant obstacle for PET tracer development given the microdosing approach used in nuclear medicine.…”
Section: Chemotypes and Available Radioligands For Mglur4mentioning
confidence: 99%
“…In this section, we would like to discuss the drug treatments that represent the closest competition to foliglurax, both for drugs acting through the mGluR4 PAM mechanism, as well as other mechanisms. From a mechanistic perspective, the closest mGluR4 enhancer competitor is the PAM valiglurax (VU2957, 15), discovered at Vanderbilt University [78,79]. A 2019 report on VU2957 characterized it as a potent, selective, CNS penetrant mGluR4 PAM, with 'attractive in vitro and in vivo pharmacological and DMPK properties across species.'…”
Section: Competitive Landscape From Multiple Perspectivesmentioning
confidence: 99%
“…Therefore, foliglurax allosteric drug target profile may not be consistent with this theory nor expected to provide reparative functional enhancement at high glutamate concentrations in PD vs. healthy. As a comparison, another advanced mGluR4 PAM compound, valiglurax (15) was reported to enhance the E MAX of glutamate in in vitro tests up to 300% of glutamate E MAX [78,79]. Lundbeck and Prexton used a newly developed PET tracer ([11C]-PXT012253), studied it in rat and nonhuman primate [76,94], and conducted a clinical study (NCT04175132) to understand and characterize the degree of receptor occupancy at the PAM site that is associated with therapeutic occupancy in nonclinical species.…”
Section: Expert Opinionmentioning
confidence: 99%
“…Similarly, the ligand (–)-PHCCC ( 3 , mGlu 4 EC 50 = 1.4 µM), originally thought to be a breakthrough, proved to be non-selective 20 , showing partial antagonist activity towards mGlu 1 receptor as well as agonist activity towards mGlu 6 34 . However, further pharmacological studies with the use of (–)–PHCCC ( 3 ) revealed its efficacy in animal models of Parkinson’s disease 7 , 20 , 33 , 35 , 38–44 , depression 45 , 46 , anxiety 47 , 48 , epilepsy 49 , 50 , neuroprotection 51 and oncology 52 but also showed a poor pharmacokinetic profile, limited brain exposure and low aqueous solubility 2 , 53 , 54 .…”
Section: Introductionmentioning
confidence: 99%
“…The first mGlu 4 PAM clinical candidate, PXT002331 ( 11 ), a chemical analogue of (–)-PHCCC ( 3 ) developed by Prexton/Domain Therapeutics 7 had very good mGlu 4 PAM potency (EC 50 = 46 nM), improved pharmacokinetics, high CNS penetration with preferential exposure in the brain, and significant anti-Parkinson’s activity in vivo in rodent models of motor symptoms of the disease, however, Lundbeck has announced in April 2020 that the phase IIa study (AMBLED) of its novel selective positive allosteric modulator of the glutamate 4 receptor, Foliglurax, for the treatment of Parkinson’s disease did not meet the primary study endpoint and the study was stopped. The second potential clinical candidate has been recently reported by Vanderbilt researches 35 . Valiglurax ( 12 ) represents an isoquinoline-based series and has shown mGlu 4 receptor PAM potency (EC 50 = 64.6 nM) comparable to PXT002331.…”
Section: Introductionmentioning
confidence: 99%