G protein-coupled receptors (GPCRs) are an important and long-standing family of drug targets. Despite many historical success stories, today there are still a significant number of GPCRs with compelling pre-clinical validation that remain highly challenging for drug discovery. Over the last 8 years there has been significant progress in the structural biology of GPCRs facilitating Structure-Based Drug Design (SBDD) approaches. Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a precisely defined biologically-relevant conformation. StaR® proteins are amenable to techniques that cannot be readily used with wild-type GPCRs, including fragment screening, biophysical kinetic profiling and X-ray crystallography. There is currently a major unmet medical need in the treatment of Alzheimer’s disease, where current agents typically offer only modest and transient cognitive benefit. Muscarinic M1 receptor agonism has shown clinically efficacy in the treatment of both Alzheimer’s dementia and cognitive impairment associated with schizophrenia, yet previous compounds lacked the necessary selectivity against receptor sub-types and resulted in undesired cholinergic side effects. Utilizing the proprietary StaR® technology the structures of both muscarinic M1 and M4 receptors in their agonist conformations have been solved, with multiple agonist ligands, and will be disclosed. These structural insights have been instrumental in the design of highly selective M1 agonists with good ligand efficiency and drug-like properties. The chemical structure, SAR development and in vivo pharmacological data of a series of highly selective M1 agonists will be disclosed. This work has led to the first highly selective M1 agonist candidate (HTL9936) to entered clinical trials.

Discovery and clinical progression of highly selective M1 agonists utilizing structure-based drug design

254th National Meeting (2017)

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