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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In this first installment of our two‑part Pharm to Table special on MK‑7845, Dani and LC sit down with medicinal chemist Valerie Shurtleff to unpack the discovery journey behind this 3CL protease inhibitor—from early structural insights to an unexpectedly effective difluorobutyl isostere. Val walks us through how the team balanced potency, VLE, metabolic challenges, and design intuition to land on a well‑rounded preclinical candidate - one of the most dynamic programs of her career. Along the way, she reminds us why asking good questions, collaborating relentlessly, and occasionally surviving a “Hot Ones” challenge are all essential scientific skills. It’s an episode packed with chemistry, creativity, and just enough fluorine to keep things spicy.

Stay tuned for Part 2, where we shift from invention to implementation and explore how the process chemistry team brought MK‑7845 to life at scale.

Read some of the papers we discussed today:

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic - J. Med. Chem.

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Join us for a conversation with Yining Ji Chen, recipient of the 2025 ACS Rising Star Award, on how mechanistic insight powers innovation in pharmaceutical process research. We dive into her career journey and standout projects—from Pd-catalyzed C–N coupling for HCV therapy to dynamic phosphorylation in nucleotide synthesis—plus her creation of LED‑NMR for real-time photochemical reaction monitoring. Hear how deep mechanistic understanding drives robustness and safety, why she moved to the Data‑Rich Measurements group, and which emerging analytical technologies excite her most. A celebration of scientific rigor shaping efficient, reliable pharma processes!

Read some of the papers we discussed today:

A multifunctional catalyst that stereoselectively assembles prodrugs - Science

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions - Chem Sci

LED-Illuminated NMR Spectroscopy: A Practical Tool forMechanistic Studies of Photochemical Reactions - ChemPhotoChem

From at-line to online NMR: coupling probe-based autosampler with benchtop NMR - Reaction Chemistry and Engineering

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In this episode, Dani and LC welcome Jeff Moore, recipient of the 2025 ACS Affordable Green Chemistry Award, to discuss his pioneering work in biocatalysis at Merck. The conversation explores the evolution (pun intended) of biocatalytic processes in pharmaceutical manufacturing, highlighting key milestones such as the adoption of transaminases and imine reductases, and their impact on drug synthesis and sustainability. Jeff shares stories from his career, including how being 'lazy' when doing science can lead to major innovations and the practical benefits of enzyme-driven chemistry. He even leaves us with insights into the future frontiers of biocatalysis, from cascade reactions to microfluidics.

Read some of the papers we discussed today:

Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist - Organic Letters

Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture - Science

Enabling Biocatalysis by High-Throughput Protein Engineering Using Droplet Microfluidics Coupled to Mass Spectrometry - ACS Omega

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In this episode, Dani and LC interview Dr. Shane Krska, recipient of the ACS Arthur C. Cope Award, and Dr. Petr Vachal, recipient of the ACS Earle B. Barnes Award for Leadership in Chemical Research Management. Shane shares his pioneering work in catalytic methods and high-throughput experimentation (HTE) for drug discovery, while Petr discusses his leadership role driving innovation at Merck. They reflect on their career journeys from graduate school to industry, emphasizing personal growth and the importance on taking on diverse roles. We wrap it up by asking Shane and Petr what has made them the most proud over their 20+ year careers - which spans from innovations in direct-to-biology for accelerating design-make-test to advancing peptides as a modality of the future!

Read the papers we discussed today:

The Catalysis Laboratory at Merck: 20 Years of CatalyzingInnovation

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

Highly Efficient Asymmetric Synthesis of Sitagliptin

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This month we sit down with Damien Valette, Olivia Boyd and David Petrone to chat about their latest paper in Organic Letters on the desymmetrization of prochiral dienones to control all-carbon quaternary centers. This reaction leverages biocatalysis, specifically an ene-reductase [ERED] enzymes (which are making their second appearance on the pod - see S1:E5).

David, Damien and Olivia walk us through the discovery of the reaction and why it's uniquely suited to set these challenging stereocenters. This work was done in the context of work at the med-chem/process interface which we explore as well.

Damien and Olivia hail from our London UK MSD site and give us details on the progress of our company's build in the region as well as chat with us about how to be successful when collaborating with scientists on another continent (David).

Read the papers we discussed today:

HTE-Enabled Development of an Ene-Reductase-Catalyzed Desymmetrization: Remote Control of All-Carbon Quaternary γ-Centers ⁠- Org Lett 2024

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