Thursday, February 21, 2013

A Very Important Point

Driving home tonight, I happened upon a fascinating story on All Things Considered. This latest installment of Julie Rovner's series on women's reproductive health analyzes the debate between supporters and opponents of Plan B (levonorgestrel) and ella (ulipristal), two controversial emergency contraceptive measures. I'm hardly well-versed enough to take sides, but something said by one of the scientists Ms. Rovner interviewed really resonated with me (at 4:32):

"Chemically related is not chemically identical." - Dr. Diana Blithe, Contraceptive Program Director, NICHD

Well, in a word: yes! As a career medicinal chemist, I completely concur that tiny changes - say, a methyl here or a deuterium there - can have huge effects on drug potency, targeting, clearance, recognition, plasma concentration, etc, etc.

Dr. Blithe's statement rebuffed a remark made by another researcher, who said that since abortifacient RU-486 (mifepristone) and ella contained similar core skeletal structures ("chemical cousins"), they must function similarly at the same dose.

Actually, are those two drugs really that similar?

Here's ella and RU-486 side-by-side. You'll notice that the "Western" fragment (left) is identical. This probably underlies the two drugs' similar mechanisms of action (progesterone receptor competitive inhibitor) and similar active metabolites (amine demethylation).

But what about at C-17? For one, they're locally diastereomeric - the alcohol points "up" (beta) for RU-486, but the related acetate "down" (alpha) for ella. The various moieties dangling off the right side subtly change drug targeting, explains Dr. Blithe, directing effects toward the ovary (ella) or the uterine lining (RU-486). Finally, different uses (delayed ovulation vs. pregnancy termination) combined with different pharmacokinetics result in different dosing: ella sells in 30 mg tablets, while RU-486 utilizes 200 mg of active ingredient...quite a large dose for a steroid.


  1. I really like this post and think that the ideas it contains can be a great segue for writing a piece to non-chemists. Great catch, dude. And thanks to Dr. Blithe for communicating this as well.

  2. I gotta say, thank you for this post. I heard the same story on the radio, made a mental note to look up the structures when I got home, and promptly forgot to do it.