Wednesday, April 24, 2013

Okay -- Trivial Pursuit: "Will the REAL MK-5172. . . Please Stand Up?"

UPDATED | 04.24.13 @ 9:30 PM PDT:

Mystery solved -- thanks to our anonymous commenters! Great chemists one and all -- here is the proof that the PubChem database -- at NIH -- is in need of revision:

In need of revision, as well, are my graphics -- but watching an iMax of "Oblivion" has left me in need of flannel-sheeted bed rest, post haste (!) -- so a retooling of my graphics will wait for morning. Thanks, one and all!


A very alert commenter just mentioned that s/he thinks the graphic I've constructed for Merck's MK-5172 is incorrect -- that I've been using an intermediate step compound/molecule -- not the final MK-5172, in my last two posts.
So -- a simple stick drawing, at right, for easy inspection -- mine, above (click it to enlarge), PubChem's is below. They look to be the same -- to me. Is the PubChem model wrong, as well? Didn't MRL itself submit the PubChem model?

Can anyone out there enlighten us?


Anonymous said...

Unfortunately, the internet is littered with incorrect structure of MK-5172 - even the structures provided by Chinese "vendors" for MK-5172 are incorrect - but here is a link to the correct structure of MK-5172 (the actual manuscript requires subscription access, but you can see the structure in the figure provided).

Regardless, I do enjoy reading your take on all things Merck. Please keep it up

Stefan Ohlinger said...

Both of the formulas given by you and by the PubChem model does not show the real MK-5172. The side chain attached through the amide bond at the proline nucleous is missing. Also missing is the determination of absolute configuration at the chiral centers given in your formulas. Absolute configuration in MK-5172, bearing 7 chiral stereocenters could be very easily established/determined, by reading the original publications and looking, what source of chirality (L- or R-form) is used within the ex-chiral-pool synthesis of the 3 chiral intermediates a) to c). The synthesis of MK-5172 uses three ex-chiral pool synthons, a) N,O-diprotected 4-hydroxy-proline-ester, another chiral intermediate b) and c) which itself are easily obtained from ex-chiral pool synthesis from amino acids.

Stefan Ohlinger said...

Just another note: the side chain attached through the amide bond at the 4-OH-proline core in MK-5172 is essential for the protease inhibitor activity found in that class of compounds. You found this structure entity also in competitor compounds like Vaniprevir, Donoprevir and TMC-435. So the update of your formula might make it to a real HCV NS3/4A protease inhibitor.