Discovery of brain permeable 2-Azabicyclo[2.2.2]octane sulfonamides as a novel class of presenilin-1 selective γ-secretase inhibitors.

This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype complexes. A set of known PSEN-1 selective γ-Secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency.

Selective inhibitors of the PSEN1-gamma-secretase complex.

Clinical development of γ-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer's disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific γ-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition.

COVID Toes: Concurrent Lower Limb Arterial and Venous Thromboembolism in a Patient with COVID-19 Pneumonitis Presenting with Foot Ischaemia.

We present a 74-year-old gentleman, who presented with foot ischaemia requiring bilateral amputation in the absence of radiological signs of occlusive peripheral arterial disease. He was found to have COVID-19 pneumonitis and concurrent arterial and venous thromboemboli despite no initial respiratory symptoms or signs, nor pre-existing risk factors for cardiovascular disease. Patients who present with foot ischaemia with or without respiratory symptoms or signs warrant a high index of suspicion for COVID-19 infection, particularly in those with no predisposing risk factors.