What happens when the textbook SAR playbook stops working? On this episode of Pharm to Table, Rob Garbaccio joins Dani and LC to share the discovery story behind enlicitide (MK-0616), a journey filled with unusual SAR, creative problem-solving, and plenty of chemistry twists along the way. From issue-driven drug design to non-canonical amino acids and modular synthesis strategies, this conversation offers a behind-the-scenes look at how real medicines are discovered. If you're training as a chemist today, this is a story you won't want to miss.

If you enjoyed this chapter of the enlicitide story, stay tuned—we've got plenty more peptide chemistry, process development adventures, and behind-the-scenes drug discovery stories coming your way this season.

Read some of the papers we discussed today:

Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR - ⁠J. Med. Chem.⁠

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To kick off Season 5, Dani and LC discuss a recent perspective published in the Journal of Organic Chemistry that highlights innovations in synthetic chemistry which trace their origins to the work of discovering, developing and commercializing novel therapeutics. This publication was the most accessed paper published in JOC in 2025!

Dani and LC explore the motivations on writing it, its main thesis and lesson learned from reexamining nearly 75 years of chemistry innovations at Merck.

Be sure to listen through to the very end for a special Season 5 theme reveal!

Read and listen to some of the papers we discussed today:

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

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In Part 2 of our Pharm to Table deep dive on MK‑7845, Dani and LC shift from invention to implementation, welcoming process chemists Nastaran Salehi Marzijarani and Ben Turnbull to the pod. We explore how the team re‑imagined the synthesis to enable robust, scalable supply—and why a classic multicomponent reaction you probably remember from school, the Joullié–Ugi reaction, ended up stealing the show. Along the way, we unpack route selection trade‑offs, lifecycle thinking in process chemistry, and what it really takes to bring an antiviral to life at scale.

Read and listen to some of the papers we discussed today:

Asymmetric Synthesis of MK-7845, an Investigational Treatment for COVID-19 - Org. Lett.

Part 1 of MK-7845 series: SE4:E7: From Discovery to Process, Part 1: Building a 3CL Protease Inhibitor Through Smart Fluorine Placement and Design Intuition

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⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠