Medicinal chemists often face cardiotoxicity issues linked to inhibition of the hERG (human ether-à-go-go-related gene) channel. In a recent Coffee Chat, Drug Hunter CEO Dennis Hu, Director for Industry Research and Relations Dennis Koester, and Senior Scientific Editor Matt Hesse discussed ways to reduce hERG risks during lead optimization. They described approaches to reduce hERG affinity while retaining on-target potency and discussed case studies of drug programs that used these strategies to eliminate their hERG issues.

DILI is a leading cause of acute liver failure, accounting for half of these cases and often resulting in drug withdrawals. Understanding and managing DILI risk as a medicinal chemist involves exploring the intricate interplay among properties and structural features. In this article, we provide a medicinal chemist's perspective on the current understanding of DILI mechanisms, highlight cutting-edge assay developments for a holistic assessment, and discuss strategies for predicting DILI risks.

Minipigs have recently gained prominence as an alternative non-rodent in vivo model for pharmacokinetic (PK), efficacy, and toxicology studies supporting human dose predictions. This article provides an overview of the use of minipigs in small molecule preclinical drug discovery research, tracing their historical background and outlining practical considerations for selecting them in studies focusing on hepatic metabolism, oral bioavailability, CNS penetration, and toxicology. It highlights minipigs' unique advantages and makes a compelling case for their continued use in preclinical research.

Obtaining adequate drug exposure in the brain is key to treating CNS diseases effectively. Recently, Dennis Koester gave us a crash course in CNS drug discovery in a Drug Hunter Flash Talk. Here, he sums up some key points on how to find compounds that cross the blood-brain barrier.

Dian Su’s journey from chemistry and proteomics to the DMPK of drug conjugates Following a different path comes naturally to Dian Su, Senior Director of DMPK at Bicycle Therapeutics. From a childhood in a small village in China’s northeast Shandong province to her work examining the drug metabolism and pharmacokinetics (DMPK) of antibody-drug [...]

Today, ozanimod is a likely megablockbuster drug approved for ulcerative colitis and multiple sclerosis. But before it became the first S1P modulator approved in ulcerative colitis, it received a scary, headline-making “ Refuse to File ” letter from the FDA due to insufficient preclinical characterization of an active metabolite RP112273 [...]

This article explains what Phase II drug metabolism is, contains a poster summarizing common enzyme-mediated bioconjugation reactions, and provides interesting examples of Phase II transformations and their impact on drug pharmacology. "As any biotransformation scientist will know, metabolism is not a binary function, and drugs can be cleared [...]

Optimizing lead compounds to have drug candidate-like qualities is time-consuming and expensive. Oftentimes, critical drug discovery project questions, such as on-target pharmacology or toxicology, can be answered more efficiently with compounds that are "good enough," saving teams time and further resource investment. This article discusses [...]

In this minireview, Drs. Jayme L. Dahlin and Michael A. Walters summarize the different mechanisms by which molecules can be AICs (assay interference compounds), a subset of which can be flagged as PAINS (pan-assay interference compounds) by a popular set of substructure filters. They bin these into non-technology-related interference [...]

Small-molecule drug candidates are increasingly falling “ beyond the rule of 5 ,” making oral administration more challenging. Optimizing a drug’s solid form can improve its solubility and bioavailability when further molecular modifications are prohibitive. This minireview covers solid form strategies for increasing the solubility and oral [...]

This article explains what Phase I drug metabolism is, contains a poster summarizing common enzyme-mediated drug metabolism reactions, and provides interesting examples of phase I biotransformations and their impact on drug pharmacology. By Drake Anthony Russell , reviewed by Dr. Dian Su and Dr. Julia Shanu-Wilson. Thanks to Hypha Discovery [...]

Assume a cow is an evenly distributed sphere... sometimes. I happened to take an animal physiology course in college because my girlfriend (now wife) needed it for her biology major and taking a class together about bird metabolism was my idea of a nice date.  I had no idea it would end up being one of the most useful courses in my career [...]

Having a clinical drug-induced liver injury (DILI) signal is a surefire way to kill a drug candidate in non-serious indications like pain or chronic indications like diabetes, and will even give oncologists second thoughts as cancer patients are living longer. What can we do to prevent it? Plan A: Small Pill and No Greaseb ombs A widely [...]

With the biochemistry magic available to the liver, it's a wonder that anything we consume is well-tolerated. Even carboxylic acids are structural alerts as they can be converted to bioreactive acyl glucoronides. The best we can do as drug hunters is minimize the risk of toxic metabolite formation and apply assays appropriately to select [...]

This article contains a pharmacokinetics reference table ("PK cheat sheet") with common cross-species physiological parameters relevant to PK, including animal size, liver blood flow, kidney blood flow, and body volumes. When interpreting compound pharmacokinetic (PK) data, it's helpful to have reference values to compare experimental data to [...]