The molnupiravir discussion last week revealed to me a woeful gap in my nucleoside prodrug knowledge. Spurred on by @GusTheChemist, I've been working to close that gap.
Never be ashamed to admit when you don't know something. These are the best opportunities to learn! 1/4
Gus got my reading rolling with this review on phosphate and phosphonate prodrugs. Putting that first phosphate on in vivo is slow, so having it already present is a strategy. 2/4 pubs.acs.org/doi/10.1021/cr…
Here's another review that's more general and spends considerable time on various ester prodrugs, including amino acid esters. 3/4 jpharmsci.org/article/S0022-…
And... I was already able to deploy some of this knowledge this week to address why valine is useful! 4/4
🧵 I won’t wade too far into the debate du jour re: the Nobel and Hajos (who is alive), Parrish, Eder, Sauer, and Wiechert. But maybe a slight aside on the Hajos-Parrish ketone and its slightly larger cousin, the Wieland-Miescher ketone. 1/
The Hajos-Parrish and Wieland-Miescher ketones have had a big impact on steroid synthesis. They’re still central to teaching organic synthesis in the first year of grad school (AFAIK). 2/ en.wikipedia.org/wiki/Wieland%E…
It’s not clear to me that the asymmetric Hajos-Parrish and Wieland-Miescher ketone syntheses were, by themselves, enough to unlock the tumblers of the organocatalysis universe. Otherwise, why did it take another ~30 years to get around to it? 3/
Time for another PK tweetorial, this time featuring a deeper dive on the not-so-mystical art of human dose prediction. 1/
I’ve argued previously that human dose is the master optimization parameter in medicinal chemistry. Like death, it can’t be cheated. All variables come together in this one number. 2/
This earlier thread talks about some of these things at a higher level and is worth a review. 3/
🧵By request, here we go with another PK tweetorial, this time on the free drug hypothesis. 1/
References up front. A great one on how to properly use plasma protein binding (PPB) to interpret PD/efficacy data and NOT use PPB as an optimization parameter. This paper is a true classic. I’ll never be able to fully repay the debt I owe to it. 2/ nature.com/articles/nrd32…
I support our group with early human dose prediction. Not the fancy, need-tons-of-software and a DMPK pro kind. Just the kind that uses some basic algebra. HDP is a unifying concept for med chemists. It’s the master optimization parameter, and it can’t be easily cheated. 1/
Here’s a wonderful paper from AstraZeneca that speaks to this conceptual framework - this isn’t something I invented. The concept has been around for years. Required reading! 2/ pubs.acs.org/doi/10.1021/mp…