gamma-Secretase is an enzyme complex that is linked to the formation of amyloid plaques. This is why gamma-secretase is an important target for therapeutic intervention. The trouble is, known inhibitors of gamma-secretase interfere with cell-surface receptor called Notch, and inhibition of its processing is understood to be detrimental. Earlier, Merck had developed a series of gamma-secretase inhibitors, whose activity was attributed to equatiorial placement of the sulfone substituent (the axial congener was found to be inactive). There is an interesting paper in J. Med. Chem. that documents recent efforts in this program. The newly created analogs are much more effective in forcing the sulfone to occupy the desired equatorial position. How is this accomplished, you might ask? Take a look at the compound in the grey box below… When it gets close to impossible to draw a neat looking structure in ChemDraw, I know that I am dealing with one ugly molecule. I refer to how the C-F bond is depicted (if drawn straight down, it would encroach on the sulfone unit). Putting trivial matters aside, this compound is a really interesting example of problem-solving in conformational analysis. That is on one hand… On the other hand, this polycycle proves that there is just so much room for improvement in organic chemistry. I specifically refer to the dearth of atom-economical methods to enforce conformational states.Those who think this area of inquiry has matured are dead wrong. The monster in grey box features an interesting nugget: the phosphorus-containing ring. As a matter of fact, I was drawn to this paper due to this unusual heterocycle, an area that is of great interest to my lab at the moment.