ACT-462206

Brain orexin system hyperactivity contributes to neurogenic hypertension. We previously reported upregulated neuronal kinin B1 receptor (B1R) expression in hypertension. However, the role of central B1R activation on the orexin system in neurogenic hypertension has not been examined. We hypothesized that kinin B1R contributes to hypertension via upregulation of brain orexin-arginine vasopressin signaling. We utilized deoxycorticosterone acetate (DOCA)-salt hypertension model in wild-type (WT) and B1R knockout (B1RKO) mice. In WT mice, DOCA-salt-treatment increased gene and protein expression of orexin A, orexin receptor 1, and orexin receptor 2 in the hypothalamic paraventricular nucleus and these effects were attenuated in B1RKO mice. Furthermore, DOCA-salt- treatment increased plasma arginine vasopressin levels in WT mice, but not in B1RKO mice. Cultured primary hypothalamic neurons expressed orexin A and orexin receptor 1. B1R specific agonist (LDABK) stimulation of primary neurons increased B1R protein expression, which was abrogated by B1R selective antagonist R715 but not by the dual orexin receptor antagonist, ACT 462206, suggesting that B1R is upstream of the orexin system. These data provide novel evidence that B1R blockade blunts orexin hyperactivity and constitutes a potential therapeutic target for the treatment of salt-sensitive hypertension.

This paper summarizes a personal perspective on key learnings from projects the author was involved in over the last 20 years. For example, the discovery of macitentan, the most successful molecule to date from this personal collection, marketed by J&J for the treatment of pulmonary arterial hypertension (PAH). [1] Then the discovery of ACT-462206, a dual orexin receptor antagonist for the treatment of insomnia disorder with a serendipitously short story from the screening hit to the drug [2] followed by the identification of daridorexant, another dual orexin receptor antagonist. Daridorexant successfully passed first pivotal phase 3 clinical trial in April 2020 for the treatment of insomnia disorder [3] ("Good things come to those who wait"). Finally, ACT-451840, an antimalarial drug with a novel mechanism of action, identified in the perfect collaboration between academia and industry. The compound is in phase 2 clinical development. [4] In addition, the importance of the screening compound collection is briefly discussed, as a key asset for drug discovery. The measures Idorsia implemented to obtain valuable hits from high-throughput screening (HTS) campaigns are elaborated. [5] Drug discovery is a multi-disciplinary business with unlimited exciting challenges asking for excessive optimism when tackling them in a playful manner.