Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754

The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.

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Publication Details

Journal
Organic Process Research & Development
Published
2025-03-06
DOI
https://doi.org/10.1021/acs.oprd.4c00539
Citations
4
Primary Topic
Click Chemistry and Applications
Type
article
Field-Weighted Citation Impact
3.74
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article

Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754

Kevin P. Cole, Spencer B. Jones, Brian M. Watson, Howard B. Broughton et al.
4 citations
Organic Process Research & Development
Click Chemistry and Applications
3.74
article

Preclinical Toxicology Supply for a Complex API Enabled by Asymmetric Catalysis and Rapid Chemical Development: IL-17A Inhibitor LY3509754

Kevin P. Cole, Spencer B. Jones, Brian M. Watson, Howard B. Broughton, J. Eugenio de Diego, Katherine M. Partridge, William Holloway, Graham R. Cumming, Peter A. Lander, Thomas J. Beauchamp, H. George Vandeveer, Talbi Kaoudi, David A. Coates, Kwame Frimpong, J. Craig Ruble, S. Saouane, Adam M. Levinson, Charles Lugar, Yu Lu, J. Gutierrez, Ian Hotham, Narasimha Rao Ummaneni
article en
4 citations

Abstract

The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2–sp3 C–C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.

Organic Process Research & DevelopmentVol. 29(3)
Eli Lilly (United States) (US), Albany Molecular Research (United States) (US), Eli Lilly (Spain) (ES)
Openalex Percentile: Top 8%
Click Chemistry and Applications
3.74
DOISourceOpenAlex
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