20 Years of Medicinal Chemistry – Always Look at the Bright Side (of Life)

Abstract

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.

Hypocretins (orexins): The ultimate translational neuropeptides

“…ACT‐462206 [49], which was investigated in Phase I studies, but stopped [32, 73], provided a valuable chemical starting point that led to the discovery of ACT‐541468/daridorexant [50, 73]. Daridorexant (Idorsia Ltd.), currently in Phase III, is a highly potent DORA, developed based on PK/pharmacodynamic modelling to improve both the onset of action and clearance commensurate with an 8‐h sleep period in humans and to provide an increase in NREM and REM similar to natural sleep as seen in preclinical species [30, 50].…”