Jean-Philippe Rocher

mGluR5 Negative Allosteric Modulators Overview: A Medicinal Chemistry Approach Towards a Series of Novel Therapeutic Agents

Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.

Discovery of 1,5-disubstituted pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.

Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.

Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep-wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones.

A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2). Identification and synthesis of N-propyl-5-substituted isoquinolones

A series of N-propyl-5-substituted isoquinolones was identified as positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) via high-throughput screening (HTS). The subsequent synthesis and preliminary SAR exploration that led to the identification of compound 20 are described.

Recent advances in drug discovery of GPCR allosteric modulators for neurodegenerative disorders

&NA; The activation or the inhibition of G‐protein coupled receptors (GPCRs) implicated in the pathophysiology of neurodegenerative disorders is considered as a relevant approach for the treatment of these diseases. The modulation of the relevant GPCRs targets by positive or by negative allosteric modulators appears to be promising, the major challenge remaining the discovery of these molecules. In this review, we highlight the recent development in this field and the therapeutic potential of selected GPCRs allosteric modulators.

A novel series of metabotropic glutamate receptor 5 negative allosteric modulators based on a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine core.

A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.

mGluR2 Activators and mGluR5 Blockers Advancing in the Clinic for Major CNS Disorders

Abstract Metabotropic glutamate receptors (mGluRs) belong to the Class C G-protein coupled receptor and are activated by glutamate, a major neurotransmitter in the brain. The widespread expression of mGluR, in particular, mGluR2 and mGluR5 subtypes, throughout the central nervous system has made those two receptors attractive therapeutic targets for the treatment of severe neurological disorders, such as schizophrenia, anxiety, Parkinsons disease levodopa-induced dyskinesia, fragile X syndrome, and major depressive disorders. This review therefore focuses on the drug discovery efforts and clinical status of mGluR2 activators acting as orthosteric agonists or positive allosteric modulators as well as negative allosteric modulators of mGluR5.

New technologies enabling the industrialization of allosteric modulator discovery

Allosteric modulators (AMs) are a promising avenue towards safe and selective drugs. AMs can interact selectively with unique domains distinct from the endogenous ligand binding site of receptors, up- or downregulating the response to receptor activation. Emphasis is placed in this article on the latest development in high-sensitivity technologies designed to identify AMs of G-protein coupled receptors. In addition to new pharmacological approaches, encouraging results in the crystal resolution of these targets enable use of more rational approaches to identification and optimization of AMs.