Ketohexokinase (KHK) inhibition has shown potential as a treatment for non-alcoholic steatohepatitis (NASH) and non-alcohol fatty liver disease (NAFLD). As the KHKi program at Pfizer narrowed in on lead matter for clinical development, multiple compounds were profiled in parallel and a robust plan was created to both allow time for data generation and for optimization of the synthesis of multiple leads for large scale without having to adjust timelines. Strategic planning to enable bulk delivery of multiple compounds along with the necessity for crisp decision making to balance long-term optimization with short term delivery goals allowed the team to position for efficient access to the clinical candidate. The triaging of lead matter and the synthesis of key compounds will be presented including the enablement of key monomers: 2-methyl azetidine and [3.1.0] amino ester which were used to access &gt;300 g of the clinical candidate to support pre-clinical efficacy and safety studies.

Optimization of the chemical matter and synthesis leading to a ketohexokinase inhibitor clinical candidate

255th National Meeting (2018)

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