As a result of our efforts to discover novel p53:MDM2 protein–protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.

Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases.

Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology of the orthosteric binding site, many drug candidates resulted in limited clinical success. Although several advances in treating peripheral pathologies have been achieved, targeting CNS pathologies remains challenging for researchers. Nevertheless, significant progress has been made in recent years to develop functionally selective orthosteric and allosteric ligands targeting the mAChRs with limited side effect profiles. This review highlights past efforts and focuses on recent advances in drug design targeting these receptors for Alzheimer’s disease (AD), schizophrenia (SZ), and depression.

/pdf/drug-design-targeting-the-muscarinic-receptors-and-the-3t24igw2.pdf

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.

Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres.

Recent disclosures of clinical candidates. Highlights from the Society of Medicines Research Symposium, held December 4, 2014 - National Heart & Lung Institute, London, UK

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Fragment-based drug discovery for allosteric sites, PPI’s... and the future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Targeting protein−protein interactions using small-molecule fragments and an antibody platform . . . . . . . . . . . . . . . . . . . . . . 149 Antibodies as tools in NCE discovery . . . . . . . . . . . . . . . . . . . . . . . 150 Challenges and opportunities in allosteric enzyme inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Phenotypic screening approaches for the discovery of novel antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Bicycles: high affinity bicyclic peptides from phage display libraries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Leading into new spaces – strategies for lead generation in neuroscience medicinal chemistry . . . . . . . . . . . . . . . . . . . . . . . . 154 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

From targets to candidates: emerging strategies in drug discovery. Highlights from the Society of Medicines Research Symposium, held on December 12th, 2013 - National Heart & Lung Institute

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Recent disclosures of clinical candidates. Highlights from the Society of Medicines Research Symposium, held December 4, 2014 - National Heart & Lung Institute, London, UK

From targets to candidates: emerging strategies in drug discovery. Highlights from the Society of Medicines Research Symposium, held on December 12th, 2013 - National Heart & Lung Institute