Honing Halophilicity

Let's say you have a late-stage drug candidate, with an alcohol, an olefin, and a pyridine. Now you toss in one equivalent of a chlorinating reagent.

Which functional group gets halogenated first?

Babak Borhan and colleagues from Michigan State and Dow may have your answer. In a recent JACS full article, they disclose the HalA (halenium affinity) scale, a DFT-calculated delta to describe the relative reactivity of various groups to an incoming halogen source. They back up their calculations with NMR competition studies, showing, for example, that two structurally similar molecules have a rather skewed 7:1 equilibrium, as predicted by a 1.1 kcal / mol difference in HalA:

Borhan et. al., JACS 2014

Using 500 computationally-evaluated functional chlorenium "acceptors" (Lewis bases), Borhan and colleagues create a chart to help answer our initial question: What reacts first?

I'm certain even more detailed versions of this chart are currently underway. I wonder how well it would extend to prediction of methyl or trifluoromethyl group additions?

More Fun with Google NGram

I know it's not perfect, but I get a real kick out of searching Google NGram Viewer for scientific terms. While discussing the difference between "analogue" and "analog" as they relate to drugs, Chemjobber sent over the NGram comparing their usage.

Once more, I found myself falling down the NGram rabbit hole...

Derek Lowe's played with this a bit over at Pipeline. One thing his commenters wanted to highlight? Carbene. Turns out, when the first neutral lone pair appeared on carbon (around 1910), not many people wrote it down as such. When v.Eggers-Doering and Simmons / Smith began incorporating carbenes into organic synthesis in the mid-'50s, BOOM! They exploded onto the scene:

Vitamins, which were virtually unknown as food additives impacting human heath in the 1800s, were rapidly identified by the early 1900s. In just 20 short years, they went from nonexistent to appearing three out of a hundred thousand published words:

When van Leeuwenhoek first peered through his first microscopes, he called the protozoa, bacteria, amoebae, and various other biology "animalcules." This persisted for a few centuries, until Pasteur and Koch began to advance the germ theory. The result? In just a few short years, microorganisms - both literal and literary - took over:

Readers - Play around, and tell me if you can find some more fun trends! 
I'll update accordingly...

Update (6/8/13) - Thanks Andrew, 0.001% is NOT 1 our of a thousand (D'oh!)

A Jump to Conclusions...Based on Data?

Nature Reviews Drug Discovery recently released a spate of articles recapping the tumultuous past decade in drug development. 

I'd like to highlight a specific article, titled "From the Analyst's Couch - A Decade of Drug Discovery." Written by one John Arrowsmith (of Thomson-Reuters data-crunching fame), it shows how the major players in the pharma biz have juggled around in the past 10 years. Note Roche and Novartis' upward trend: from 2001-2011, Roche went from 10th to 5th in market cap, and Novartis from 5th to 3rd.

Source: Thomson Reuters

Not bad at all. Any specific reasons behind those climbs? First, Roche's acquisition of Genentech certainly helped them out, with less of the messy transitions of the Pfizer-Wyeth or Merck-Schering mergers. Second, look at the massive uptick in R&D spending by Roche (blue) and Novartis (pink) over the past decade! 

Unless I'm mistaken, I read both companies' spending as roughly quadrupling, from ~$2 billion to nearly $8-9ish billion over the past decade. Wow.

Note also that Pfizer, making double their Lipitor take from a decade past, still showed mostly flat investment in R&D from 2003-2009.

Page Two shows us a bar graph of the radical shift in therapeutic areas (this include all drugs from P1 -> NDA). 

Source: Thomson Reuters

Looks like cancer meds / pain / diabetes are WAY up, and cardiovascular is way down. 

Perhaps another sign of a graying population? Readers, what's your take?