Macrocyclic molecules, containing 12 or more atoms in a ring system, are increasingly prevalent in drug discovery, with over 67 macrocyclic drugs approved so far and several notable examples of clinical success highlighted on Drug Hunter recently, including MK-0616 , repotrectinib , and pacritinib . By imparting conformational restraint and [...]

This “journal club” article highlights five recent articles of general interest to drug discovery scientists, including reviews on therapeutic areas of interest, principles and areas of medicinal chemistry and pharmacology, and a synthetic transformation worth keeping in mind. 1. A “Magic Chloro” Med. Chem. Review D. Chiodi and Y. Ishihara [...]

Drug candidates exhibiting atropisomerism are often considered challenging for development by pharmaceutical professionals from synthetic and regulatory perspectives. Molecules that exist as stable atropisomers can be acceptable for development, but are often difficult to synthesize in their isomerically pure form. Modern catalysis [...]

In this guest article, Dr. Luíza Cruz breaks down the synthesis of Gilead’s lenacapavir (GS-6207), Drug Hunter’s Small Molecule of the Year – 2020 . Lenacapavir is a promising first-in-class, long-acting injectable (LAI) HIV capsid inhibitor . Interesting synthetic steps employed in this route include an unusual sodium chlorite-mediated [...]

The gem-dimethylcyclopropyl group is a key element in drugs, candidates, and agrochemicals, with a recent example being nirmatrelvir, the active ingredient in the Pfizer COVID-19 drug, Paxlovid. Here, we review synthetic strategies used to produce the key gem-dimethylcyclopropylproline intermediate, which may now be required in hundred-ton [...]

We all knew process scientists were good, but the Merck and Codexis teams just took it to another level!  Unnatural nucleosides like Merck’s reverse transcriptase inhibitor islatravir ( 1 , Figure 1) are well-known to be challenging to synthesize by traditional methods, as evidenced by several published chemical syntheses [...]

There are catalysis geniuses (looking at you, process chemists!) and then there are those of us just looking to put compounds in vials.  Here are the simplest conditions that'll get you what you want 90% of the time.  Beyond that you'll need to ask a guru like Nick White or Malcolm Huestis. Hope this table helps. Explore drughunter.co m for more.

Scientists from GlaxoSmithKline’s Stevenage site have an excellent article in J. Med. Chem. showing that cyclopropyl pyran (CPP) groups can serve as viable isosteres to N-pyrimidyl morpholines thanks in part to favorable cyclopropane σ -> aryl π interactions. N -aryl morpholines are privileged motifs in drug discovery, and suitable [...]

BMS-986142 is a reversible BTK inhibitor with two axial stereocenters.  BMS synthetic chemists were able to make >200 kilos of this compound as a single isomer using this route.  Wow. Atropisomers are a nightmare in drug discovery.  Axial stereocenters are not easy to set predictably, separation of isomers is a pain, and the products are hard [...]

Knochel's group has shown that you can fluorinate Grignard reagents without decomposition via single-electron transfer reactivity (SET) by a simple solvent switch from THF to DCM. A common way to prepare aryl fluorides is through lithium-halogen exchange, followed by trapping with N-fluorosulfonimide (NFSI).  This isn't always viable, as the [...]