Discovery of VU6028418: A Highly Selective and Orally Bioavailable M₄ Muscarinic Acetylcholine Receptor Antagonist

Abstract

Herein, we report the SAR leading to the discovery of VU6028418, a potent M 4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.

2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery

“…In addition to 5-HT 2A and other GPCRs, the current list of biological targets deemed “anti” is broad and includes kinases, ion channels, cytochrome P450s, and efflux pumps . Perhaps the most well-known and frequently encountered antitarget in the drug discovery literature is the human Ether-à-go-go-Related Gene, or the hERG channel. − hERG is a potassium ion channel expressed in cardiac tissue, and it plays a critical role in the regulation of the heart’s electrical activity . Specifically, disruption of hERG is associated with the development of potentially fatal Long QT Syndrome (LQTS), an unnatural lengthening of the QT cardiac repolarization interval …”

Dystonias: Clinical Recognition and the Role of Additional Diagnostic Testing

“…132 Promising new agents on the horizon that require additional human studies include ritonavir and VU6028418. 133,134 Ritonavir, which is FDA approved to treat HIV, is hypothesized to act via promoting the integrated stress response within cells, which has been shown to be abnormal in DYT1 cell lines. 133 VU6028418, a highly selective M4 muscarinic acetylcholine receptor antagonist, may have less side effects than trihexyphenidyl.…”

“…134 VU6028418, a highly selective M4 muscarinic acetylcholine receptor antagonist, may have less side effects than trihexyphenidyl. 135 Thus, it is likely that new oral agents and different serotypes of botulinum toxin will become available in the coming years.…”

Deuterium in drug discovery: progress, opportunities and challenges

“…Inhibition of cytochromes is undesirable in drug R&D as it might lead to drug–drug interactions in patients undergoing multiple therapies. Very recently, a few reports have highlighted that deuterium incorporation might reduce the time-dependent inhibition of CYP enzymes, although the reason behind this effect is still not clear (for example, BMS-986144 140 ,VU6032952 141 and d 3 -clopidogrel 142 , 144 ).…”