Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.
Here’s a caution from a new paper out of Manchester. The group had been synthesizing inhibitors of PARG (poly-ADP ribose glycohydrolase), an enzyme involved in DNA repair. The general chemotype is shown at right, but there are a number of variations. That fluorine is a new addition, though. The corresponding cyclopropylmethyl se… Read More
As anyone who’s been following the oncology field knows, antibodies against either the PD-1 receptor or its ligand PD-L1 are about the biggest things going in the field right now. Hundreds of clinical trials are underway against various tumor types and in various combinations, in the effort to see how far the immuno-oncology idea can… Read More
One of the impressive things about biochemistry and cell biology is how it can produce physical correlates to things that we know and experience, but have no detailed explanation for. There’s a really interesting example out in Cell that has to do with the effects of sunlight on mood and learning. Those effects are real, but… Read More
Medicinal chemists spend a lot of time thinking about the relative greasiness of their molecules. Being professional scientists, of course, we have come up with some slightly more quantitative phrases than “relative greasiness”, but that’s definitely the idea. How hydrophilic/hydrophobic a compound is determines not to what extent… Read More
You know that a technique has attained wide currency when the vendors start selling reagents and tools around it. Here’s an example in the protein degradation field: a team at Promega (well-known vendors of assay reagents and kits) report a new system to evaluate the extent and time course of protein degradation compounds. For those… Read More
Pharmacokinetics – the study of how drugs are taken up, distributed, metabolized, and cleared – is obviously a key part of drug development. Every drug substance gets handled somewhat differently by the human body, and these differences can completely determine whether you’ve got an effective therapy or not. But the tools we have… Read More
Just what is going on at Celgene? They’ve had some odd recent setbacks (such as as the failure of Mongersen), and another such acquisition, Ozanimod, had its filing recently rejected by the FDA. Several things about that incident were eyebrow-raisers – for one, it’s rare for a large, established company to get an outright refusal- Read More
Here’s an update to a post from last year about silicon in drug-like molecules. The Denmark group at Illinois has investigated a range of silicon-containing heterocycles, providing both synthetic routes into the (mostly unknown) structures, and looking at some basic pharmaceutically relevant properties. There’s a lot of work in this pap… Read More
Here’s another solid pharmacokinetics paper, this one from Genentech, with advice on how to extend drug half-life (compare this other recent one). They’re specifically addressing the “make it less lipophilic” rule of thumb that many medicinal chemists have, and they demonstrate that this isn’t exactly a universal law.… Read More
Here’s a solid med-chem paper from Merck on the topic of extending half-life for small-molecule drugs. This obviously is most important (and can have the biggest effect) if your compound has a short half-life after dosing to begin with (and plenty of compounds do). As the paper notes, if you have constant clearance for the… Read More
