Identification of 'hit to lead' small molecule biased' apelin receptor agonists for treating pulmonary arterial hypertension (PAH) using HTS and molecular modelling. (360G-Wellcome-107715_Z_15_Z)

(a) PAH is a devastating disease with 15% mortality per year under existing treatments1. Current drug therapy has significant limitations including side effects therefore considerable commercial opportunity exists owing to high unmet need for safer, more efficacious medicines. (b) Compelling evidence from extensive validation studies in our first in human studies9 and animal models of PAH (see Q10) suggests biased apelin agonists would give desired beneficial vasodilatation, positive inotropic action and re-modelling of the heart, without desensitizing the receptor and with a superior side effect profile. (c) The key goal of the project and deliverables will be active hits suitable for hit to lead development of a 1st in class small molecule treatment for PAH as a monotherapy or in combination with endothelin antagonists. (d) A major impact on the symptoms of PAH is expected, dramatically improving functional exercise capacity beyond existing therapies and