The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core

Abstract

This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

Restoring Agonist Function at a Chemogenetically Modified M1Muscarinic Acetylcholine Receptor

“…We selected this M 1 PAM as it has been proven to be a valuable in vivo M 1 PAM tool compound with suitable pharmacokinetic properties and devoid of adverse effect liability in rodents. 18,19 As shown in Figure 8, the hM 1 DREADD mice showed a hyperactivity phenotype compared with the hM 1 WT mice. This is consistent with our previous findings where the M 1 DREADD mice were hyperactive, similar to the M 1 knockout (KO) mice.…”

“…To provide a proof-of-concept that M 1 PAMs can activate M 1 DREADD receptors in vivo , we performed an open-field test on humanized M 1 WT and M 1 DREADD mice 30 min after the injection of either vehicle or VU0486846 (10 mg/kg). We selected this M 1 PAM as it has been proven to be a valuable in vivo M 1 PAM tool compound with suitable pharmacokinetic properties and devoid of adverse effect liability in rodents. , As shown in Figure , the hM 1 DREADD mice showed a hyperactivity phenotype compared with the hM 1 WT mice. This is consistent with our previous findings where the M 1 DREADD mice were hyperactive, similar to the M 1 knockout (KO) mice .…”

Activation of M1muscarinic receptors reduce pathology and slow progression of neurodegenerative disease

“…Here we substantially extend these earlier studies using global proteomic and transcriptomic analysis of murine prion disease to report that this model shows adaptive-responses, including neuroinflammation and up-regulation of protein markers of AD, as well as indicators of synaptic loss and mitochondrial dysfunction, that are characteristic hallmarks of AD. We further report that the next generation M1-PAM, VU0486846 (VU846) 26,27 , reduced markers of neuroinflammation and prevented the up-regulation of adaptive disease responses whilst maintaining synaptic proteins at near normal levels. These observations offered mechanistic insight into the improvement in behavioural symptoms and the extension of survival of prion-diseased mice associated with administration of M1-receptor PAMs.…”

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

“…Excitingly, the amino acid residues of this extracellular allosteric site of the mAChRs show greater diversity between the different subtypes, thus providing the framework for designing mAChR subtype selective allosteric ligands. In fact, the allosteric sites of the M 1 and M 4 mAChRs have successfully been targeted by rationally designed synthetic allosteric ligands, with (now) a large number of subtype selective allosteric ligands available as pharmacological tools (Ma et al, 2009;Kuduk et al, 2010;Kuduk et al, 2011;Salovich et al, 2012;Le et al, 2013;Mistry et al, 2013;Croy et al, 2014;Huynh et al, 2015;Davoren et al, 2016a;Mistry et al, 2016a;Wood et al, 2016a;Davoren et al, 2016b;Mistry et al, 2016b;Wood et al, 2016b;Wood et al, 2017a;Wood et al, 2017b;Davoren et al, 2017;Long et al, 2017;Tarr et al, 2017;Bertron et al, 2018;Beshore et al, 2018;Dallagnol et al, 2018;Engers et al, 2019a;Engers et al, 2019b;Chopko et al, 2019;Jorg et al, 2019;Poslusney et al, 2019;Schubert et al, 2019;Temple et al, 2019;Temple et al, 2020a;Temple et al, 2020b). Since the orthosteric and allosteric sites are topographically distinct, two ligands can bind one receptor simultaneously.…”

“…However, this compound was not progressed into clinical trials due to its poor solubility, limited brain penetration and high plasma protein binding properties (Kuduk et al, 2011). Subsequently, there have been substantial efforts to develop novel M 1 mAChR PAMs with improved physicochemical properties (Mistry et al, 2013;Davie et al, 2014;Kuduk et al, 2014;Davoren et al, 2016a;Mistry et al, 2016a;Davoren et al, 2016b;Mistry et al, 2016b;Panarese et al, 2016;Davoren et al, 2017;Flohr et al, 2017;Bertron et al, 2018;Beshore et al, 2018;Dallagnol et al, 2018;Engers et al, 2019b;Jorg et al, 2019;Mandai et al, 2019;Jorg et al, 2020) High M 4 mAChR-subtype selectivity was first described for the PAM, LY2033298 (Chan et al, 2008). This PAM increased the binding affinity and potency of ACh in CHO cells expressing the human M 4 mAChR, however, LY2033298 was also noted to have some activity at the M 2 mAChR (Chan et al, 2008;Valant et al, 2012b).…”