Discovery and Clinical Data for a Novel AMPA Receptor Positive Modulator

Abstract

In this chapter, a case study of a discovery project to identify potential new clinical agents for treating the cognitive deficits of schizophrenia is presented. Specifically, a hit identification and lead optimization activity is detailed for a novel series of AMPA receptor positive allosteric modulators, which ultimately delivered a clinical development candidate. The challenges of running high-throughput screening to identify positive modulators of ion channels are discussed, along with the opportunity presented by X-ray crystallography to improve the rational basis for onward analogue design. The evolution of the screening cascade, including recombinant and native tissue assays, fluorescent and electrophysiological readouts is outlined, with particular emphasis on the relevance and predictability of in vitro assays to the downstream pharmacodynamic, behavioural and tolerability screens. Additionally, the path to build confidence in the efficacy and safety profile of the clinical candidate is discussed, in light of the generic concerns of tolerability of agents that potentiate excitatory neurotransmission.