Discovery of (<i>R</i>)‑(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu₃ Selective and CNS Penetrant Negative Allosteric Modulator (NAM)

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu₃ NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu₃ IC₅₀ = 593 nM, mGlu₂ IC₅₀ >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%

Diverse Effects on M₁ Signaling and Adverse Effect Liability within a Series of M₁ Ago-PAMs

Both historical clinical and recent preclinical data suggest that the M₁ muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer’s disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M₁ activation. Efforts then shifted to focus on selective activation of M₁ via either allosteric agonists or positive allosteric modulators (PAMs). While M₁ PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M₁ ago-PAMs. Our data demonstrate that closely related M₁ PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M₁ PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M₁ responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M₁ PAMs

Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Herein, we detail the optimization of the mGlu₂ negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu₂ NAM scaffold. This new chemotype not only affords potent and selective mGlu₂ inhibition, as exemplified by VU6001966 (mGlu₂ IC₅₀ = 78 nM, mGlu₃ IC₅₀ > 30 μM), but also excellent central nervous system (CNS) penetration (<i>K</i>_p = 1.9, <i>K</i>_p,uu = 0.78), a feature devoid in all previously disclosed mGlu₂ NAMs (<i>K</i>_ps ≈ 0.3, <i>K</i>_p,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu₂ PET tracer development

Design of 4‑Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2

Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu_2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu_2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu₂ negative allosteric modulator <b>58</b> (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound <b>58</b> exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu₂ in the CNS

Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M₁ Positive Allosteric Modulators

This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M₁) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M₁ agonism, e.g., no M₁ ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL_p < 8 mL/min/kg and <i>t</i>_1/2 > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (<i>K</i>_p < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration (<i>K</i>_p > 2), despite inclusion of a basic nitrogen. Moreover, <b>24c</b> was devoid of M₁ agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M₁ PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both “medicinal chemist’s eye” and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration