AMG 176 is a drug candidate in our oncology portfolio. Ring-closing metathesis (RCM) represents a key reaction to construct its 16-membered macrocycle. High-throughput experimentation (HTE) allowed us to quickly develop a robust RCM transformation with identification of optimal reactions conditions using novel substrate and catalyst via DFT-computational analysis. With a collaboration with the Houk lab at UCLA, DFT-computational conformers analysis provided us rationalization on the studied substrates and their reactivity trends. This comprehensive process development led to a reduction in reaction volume from 800 L/kg to 50 L/kg with a &gt;20% yield compared to the discovery route, thus significantly increasing process greenness and decreasing the step e-factor. The RCM process developed from these studies was instrumental in the clinical advancement of the AMG 176 program.

Development of robust and scalable RCM process to deliver AMG 176 using HTE and computational modeling

ACS Fall 2021

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