Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor

Flohr, Alexander; Hutter, Roman; Mueller, Barbara M.; Bohnert, Claudia; Pellisson, Mélanie; Schaffhauser, Hervé

doi:10.1016/j.bmcl.2017.11.008

Cited by 5 publications

(7 citation statements)

References 19 publications

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“…One such examples is a low FS M 1 PAM, which may produce use-dependent attenuation of transmitter-signaling and avoid agonist-like behavior, a limitation of previously reported high FS PAMs. It was hypothesized that compounds with very small, yet detectable functional effects could derive from a new allosteric site . To identify such putative binding site, the team at Roche utilized a high throughput screening of the compound collection using a cell line expressing the wild-type hM 1 receptor (WT hM 1 ), followed by the use of a double Y179A-W400A mutant, corresponding to the known “gallamine/brucine site”.…”

Section: What? Allosteric Drug Modalitiesmentioning

confidence: 80%

Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases

et al. 2019

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Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. Investigations using allosteric drug candidates and chemical tools suggest that their functional effects may be tailored with a high degree of translational alignment, making them molecular tools to correct pathophysiological functional tone and enable personalized medicine when a causative target-to-disease link is known. We present select examples of functional molecular fine-tuning of allosterism and discuss consequences relevant to drug design.

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Section: What? Allosteric Drug Modalitiesmentioning

confidence: 80%

Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases

et al. 2019

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“…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).…”

Section: And M 4 Machr-selective Positive Allosteric Modulatorsmentioning

confidence: 99%

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

et al. 2021

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The M1 and M4 muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, in particular for Alzheimer’s disease and schizophrenia. Due to high sequence homology, selective targeting of any of the M1-M5 mAChRs through the endogenous ligand binding site has been notoriously difficult to achieve. With the discovery of highly subtype selective mAChR positive allosteric modulators in the new millennium, selectivity through targeting an allosteric binding site has opened new avenues for drug discovery programs. However, some hurdles remain to be overcome for these promising new drug candidates to progress into the clinic. One challenge is the potential for on-target side effects, such as for the M1 mAChR where over-activation of the receptor by orthosteric or allosteric ligands can be detrimental. Therefore, in addition to receptor subtype selectivity, a drug candidate may need to exhibit a biased signaling profile to avoid such on-target adverse effects. Indeed, recent studies in mice suggest that allosteric modulators for the M1 mAChR that bias signaling toward specific pathways may be therapeutically important. This review brings together details on the signaling pathways activated by the M1 and M4 mAChRs, evidence of biased agonism at these receptors, and highlights pathways that may be important for developing new subtype selective allosteric ligands to achieve therapeutic benefit.

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“…Recent modification around isoindolin-1-one produces compound 41 , which displays a significantly improved PAM EC 50 value of 47 nM, minimal intrinsic agonist activity, and oral bioavailability of 91% in rodents and 65% in canines . Other work in this arena includes the benzodiazepine derivative 42 , which was recently reported by a team at Roche as a selective M 1 mAChR PAM with an PAM EC 50 value of 80 nM in human M 1 mAChR expressing cells . Overall, there are variable improvements in brain exposure and in vivo efficacy for selective M 1 mAChR allosteric modulators and development continues for multiple scaffolds presented herein.…”

Section: Recent Advances In the Discovery And Design Of Class A Gpcr ...mentioning

confidence: 99%

“…120 Other work in this arena includes the benzodiazepine derivative 42, which was recently reported by a team at Roche as a selective M 1 mAChR PAM with an PAM EC 50 value of 80 nM in human M 1 mAChR expressing cells. 121 Overall, there are variable improvements in brain exposure and in vivo efficacy for selective M 1 mAChR allosteric modulators and development continues for multiple scaffolds presented herein.…”

Section: Recent Advances In the Discovery And Design Of Class A Gpcr ...mentioning

confidence: 99%

“…Among the different substitutions on C4/C5, 119 with a bromide in C5 displays higher potency than compound 112 in the kinetic binding assay (2-fold greater affinity than 112 and 3-fold less inhibition of antagonist [ 3 H]-CPX binding). 203 Compound 120 contains a 5phenyl substituent that increases potency (EC 50 ) 6-fold over 112, but when no substituent is present in the 5-position (121), allosteric enhancement efficacy is improved (77% vs 28%) along with greater antagonist activity compared to 112. 204 Additional modifications and SAR provided support for these results, and it was concluded that alkyl and aryl groups at the C4-position are favored for allosteric enhancer activity.…”

Section: Free Fatty Acid Receptors (Ffa1−ffa3)mentioning

confidence: 99%

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Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

Wold

Chen²,

Cunningham³

et al. 2018

J. Med. Chem.

117

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G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

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Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor

Cited by 5 publications

References 19 publications

Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases

Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases

Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

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