Mark Ian Kemp

A novel selective and orally bioavailable Nav1.8 channel blocker, PF‐01247324, attenuates nociception and sensory neuron excitability

NaV1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF‐01247324, a new generation, selective, orally bioavailable Nav1.8 channel blocker of novel chemotype.

Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors.

Abstract This review examines the small molecules described over the past decade as inhibitors of any of the approximately 100 human deubiquitinating enzymes (DUBs). Structures from patent publications as well as from the primary literature are included. Inhibitors of two viral DUBs are also described since these proteases share structural similarity with one of the human DUB sub-families. The structure, function and disease associations of certain DUBs are presented. The evolution of the screening assays used to identify and characterise new inhibitors is discussed. Several emerging trends in the series are highlighted and the ‘drug-likeness’ of the various inhibitors is analysed. Large pharmaceutical company collaborations have drawn attention to this field, and these recent advances are discussed in the context of the wider range of therapeutically important DUB targets.

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.

Facile chromium carbene mediated synthesis of functionalised 5- to 7-ring lactones

Abstract The reaction of pentacarbonyl[methoxy(2,6-dimethoxyphenyl)methylene]chromium(0) with acetylenic alcohols has been investigated. Reaction protocols have been optimised for rapid and direct access to functionalised γ-, δ-, and e-lactone products possessing enol ether (i.e. masked carbonyl) functionality.

Discovery and optimisation of potent and highly subtype selective Nav1.8 inhibitors with reduced cardiovascular liabilities

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we describe the discovery and optimisation of a Nav1.8 inhibiting phenyl imidazole series that delivers chemical equity that possesses high potency and selectivity and is capable of demonstrating good oral pharmacokinetics.