Investigating the orexin pathway in narcolepsy type 1 | Takeda Stories

In 2011, Takeda scientists in Shonan, Japan embarked on an ongoing journey to design and study molecules that could potentially help people with narcolepsy type 1 (NT1), a rare neurological disorder characterized in part by excessive daytime sleepiness.

Our scientists were building on the seminal discoveries made by academic researchers like Professors Emmanuel Mignot, Masashi Yanagisawa and Jerome Siegel^1-5. As we previously described using a “lock-and-key” analogy, this foundational research centered on the chemical messenger in the brain called orexin (also known as hypocretin) and its receptor that make up the biological pathway implicated in NT1.

These discoveries laid the groundwork for further scientific investigation and inspired scientists at Takeda to conduct their own research that was aligned with this “lock-and-key” concept associated with NT1. This work focused on identifying molecules of the appropriate size and shape that could be candidates for further research, with the potential to: 1) penetrate the brain and 2) interact with biological targets in the brain associated with the disease pathway.

This effort was almost like searching for a needle in a haystack. Leveraging Takeda’s extensive collection of more than one million synthetic (man-made) chemical compounds, our scientists utilized high-throughput screening (an automated method used in research to simultaneously characterize a large number of compounds) to determine which compounds had the desired structural and biological properties.

The molecules that were predicted to have the research criteria described above went through a process referred to as “lead optimization.” In preclinical research this process often involves performing multiple chemical reactions to refine the structural and biological characteristics of each molecule and evaluate its interaction with a biological target. For the small molecules that Takeda scientists were testing, the optimization process required up to twenty different chemical reactions. This required immense dedication and exceptional chemistry expertise to identify and refine these potential investigational molecules.