Contribution to the Discovery of a Novel Medicine for a Neuromuscular Disease and of other Promising Molecules for the Treatment of Neurodevelopmental and Neurodegenerative Diseases.

Hasane Ratni

doi:10.2533/chimia.2021.614

Abstract

Nervous system disorders affect millions of people around the world, through a very broad range of diseases. Here we describe our contribution to find a treatment for patients suffering from three of those diseases. The first one, autism spectrum disorder (ASD), affects approximately one in every 59 children in US. The second one, spinal muscular atrophy (SMA) is a rare disease affecting 1 in 10000 live births worldwide, often leading to death if untreated. The third one, Alzheimer's disease (AD) is a very well known devastating disease with an estimated 50 million people living with AD and other dementia, a number expected to triple by 2050. Our strategy to address those diseases was directed towards the discovery of a selective vasopressin 1a (V1a) antagonist for ASD, a splicing modifier of the survival of motor neuron 2 (SMN2) for SMA, and finally a γ-secretase modulator (GSM) for AD. In the frame of our GSM project, we also reported the discovery of a bridge piperidine moiety as a bioisostere for a phenyl moiety with an improved drug-like profile.

Highlights

Nervous system disorders affects millions of people around the world, through a very broad range of diseases
Those diseases cover an extremely broad range of incidence and prevalence as well as of patient ages, from newborn to elderly. Highlighting this diversity, we describe our contribution to find a treatment for well-known diseases such as autism spectrum disorder (ASD), Alzheimer’s disease (AD) as well as a rare disease, spinal muscular atrophy (SMA) affecting newborns, children and adults
We considered the use of a selective vasopressin 1a (V1a) antagonist for the potential treatment of ASD, which led to the discovery of two molecules, RO5028442 (1)[1] and balovaptan (2)[2], evaluated in clinic (Fig. 1)

Summary

Introduction

Nervous system disorders affects millions of people around the world, through a very broad range of diseases. Almost everyone knows someone affected by a neurological condition, which can have a profound impact on his or her day-to-day life Those diseases cover an extremely broad range of incidence and prevalence as well as of patient ages, from newborn to elderly. RO7185876; 5 to identify novel chemical matter suitable for optimization towards achieving a high selectivity and brain penetration, we decided to perform a high throughput screening (HTS). This campaign was performed using a FLIPR functional assay, followed for the confirmed hits by binding affinity determination on both human V1a and V1b receptors with a scintillation proximity assay (SPA). A systematic match pair comparison between this bridge piperidine moiety with a phenyl and the recently reported saturated bioisosteres such as bicyclo[1,1,1]pentane (BCP) or bicyclo[2,2,2]octane (BCO) demonstrates its overall favorable profile.[6]

Bridge piperidine

Alternative new cores evaluated

Panel B spacer

Conclusion