Benjamin Perry

Heteroaromatic Rings of the Future

Small aromatic ring systems are of central importance in the development of novel synthetic protein ligands. Here we generate a complete list of 24,847 such ring systems. We call this list and associated annotations VEHICLe, which stands for virtual exploratory heterocyclic library. Searches of literature and compound databases, using this list as substructure queries, identified only 1701 as synthesized. Using a carefully validated machine learning approach, we were able to estimate that the number of unpublished, but synthetically tractable, VEHICLe rings could be over 3000. However, analysis also shows that the rate of publication of novel examples to be as low as 5-10 per year. With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered.

Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines

The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.

Optimization of a series of multi-isoform PI3 kinase inhibitors.

Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.

Imidazopyridines as VLA-4 integrin antagonists

We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure-activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule.

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.

CHAPTER 10:Glutamate Receptor Modulators as Emergent Therapeutic Agents in the Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is normally associated with dopamine and other catecholamines because of the profound loss of dopaminergic neurons in the substantia nigra that is the hallmark of the disease. The need for new therapies to treat symptomatic motor and non‐motor symptoms, along with motor complications such as L‐DOPA‐induced dyskinesias (LIDs), remains an important challenge in drug discovery. Significant progress has been made recently in the development of new non‐dopaminergic treatments in the last few years, and there is substantial evidence for altered glutamate neurotransmission in PD, which may be a consequence of dopamine loss. This has generated a great deal of interest in glutamate receptor modulators for the treatment of PD. The interest initially focused on ionotropic glutamate receptors (iGluRs) both for the treatment of the symptoms of PD as well as for neuroprotective effects, and several NMDA and AMPA receptor antagonists have progressed to clinical trials. More recently, there has been substantial progress in the development of metabotropic glutamate receptor (mGluR) modulators. The recent clinical proof‐of‐concept for the treatment of LIDs with mGluR5 negative modulators has demonstrated the potential clinical significance of this approach, and positive modulators or agonists at mGluR4 also look very promising. In this chapter we will review the development and current status of compounds that modulate iGluRs and mGluRs for the treatment of PD and illustrate the challenges and opportunities that these compounds present.