Design and synthesis of novel compounds for the treatment of septic shock

Septic shock is the most severe form of sepsis and is caused by a dysregulated immune response to infection. Patients experience dangerously low blood pressure, and this is believed to be caused by the vasodilatory peptide hormone, adrenomedullin, which shows significantly elevated levels in the plasma during septic shock. Adrenomedullin causes vasodilation through binding to the adrenomedullin-1 receptor (AM1r), which is a heteromeric complex comprised of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two closely related receptors are the calcitonin gene-related peptide receptor (CGRPr) and the adrenomedullin-2 receptor (AM2r), which are formed by the association of CLR with RAMP1 and RAMP3, respectively. This work aims to develop the first small molecule antagonists of AM1r. Such compounds, that can block the binding of adrenomedullin to AM1r, have the potential to arrest the severe drop in blood pressure observed during septic shock.