Henry Rzepa's Blog Chemistry with a twist

January 14, 2018

Silicon drug analogues.

I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered the first deuterated drug receiving FDA approval last year, having first reviewed the concept back in 2009. So when someone introduced me to sila-haloperidol, I checked to see if Derek had written about it. Apparently not, so here are a few details.

(more…)

May 29, 2017

CH⋅⋅⋅π Interactions between methyl and carbonyl groups in proteins: a small molecule check.

Filed under: crystal_structure_mining — Tags: , , , , — Henry Rzepa @ 6:31 pm

Derek Lowe highlights a recent article[1] postulating CH⋅⋅⋅π interactions in proteins. Here I report a quick check using the small molecule crystal structure database (CSD).

(more…)

References

  1. F.A. Perras, D. Marion, J. Boisbouvier, D.L. Bryce, and M.J. Plevin, "Observation of CH⋅⋅⋅π Interactions between Methyl and Carbonyl Groups in Proteins", Angewandte Chemie International Edition, vol. 56, pp. 7564-7567, 2017. http://dx.doi.org/10.1002/anie.201702626

January 2, 2017

Ritonavir: a look at a famous example of conformational polymorphism.

Here is an inside peek at another one of Derek Lowe’s 250 milestones in chemistry, the polymorphism of Ritonavir.[1] The story in a nutshell concerns one of a pharma company’s worst nightmares; a drug which has been successfully brought to market unexpectedly “changes” after a few years on market to a less effective form (or to use the drug term, formulation). This can happen via a phenomenon known as polymorphism, where the crystalline structure of a molecule can have more than one form.[2],[3] In this case, form I was formulated into soluble tablets for oral intake. During later manufacturing, a new less-soluble form appeared and “within weeks this new polymorph began to appear throughout both the bulk drug and formulation areas[1]

(more…)

References

  1. J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, and J. Morris, "Array", Pharmaceutical Research, vol. 18, pp. 859-866, 2001. http://dx.doi.org/10.1023/A:1011052932607
  2. J.D. Dunitz, and J. Bernstein, "Disappearing Polymorphs", Accounts of Chemical Research, vol. 28, pp. 193-200, 1995. http://dx.doi.org/10.1021/ar00052a005
  3. D. Bučar, R.W. Lancaster, and J. Bernstein, "Disappearing Polymorphs Revisited", Angewandte Chemie International Edition, vol. 54, pp. 6972-6993, 2015. http://dx.doi.org/10.1002/anie.201410356

December 31, 2016

The “hydrogen bond”; its early history.

My holiday reading has been Derek Lowe’s excellent Chemistry Book setting out 250 milestones in chemistry, organised by year. An entry for 1920 entitled hydrogen bonding seemed worth exploring in more detail here.

(more…)

November 12, 2015

How to stop (some) acetals hydrolysing.

Filed under: reaction mechanism — Tags: , , , , , — Henry Rzepa @ 2:42 pm

Derek Lowe has a recent post entitled "Another Funny-Looking Structure Comes Through". He cites a recent medchem article[1] in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach, and acetals are famously sensitive to hydrolysis (red below). But if X=NH2, compound "G-5555" is apparently stable to acids.[1] So I pose the question here; why?

(more…)

References

  1. C.O. Ndubaku, J.J. Crawford, J. Drobnick, I. Aliagas, D. Campbell, P. Dong, L.M. Dornan, S. Duron, J. Epler, L. Gazzard, C.E. Heise, K.P. Hoeflich, D. Jakubiak, H. La, W. Lee, B. Lin, J.P. Lyssikatos, J. Maksimoska, R. Marmorstein, L.J. Murray, T. O’Brien, A. Oh, S. Ramaswamy, W. Wang, X. Zhao, Y. Zhong, E. Blackwood, and J. Rudolph, "Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety", ACS Medicinal Chemistry Letters, vol. 6, pp. 1241-1246, 2015. http://dx.doi.org/10.1021/acsmedchemlett.5b00398

January 15, 2015

A convincing example of the need for data repositories. FAIR Data.

Filed under: Chemical IT,General — Tags: , , , , — Henry Rzepa @ 2:05 pm

Derek Lowe in his In the Pipeline blog is famed for spotting unusual claims in the literature and subjecting them to analysis. This one is entitled Odd Structures, Subjected to Powerful Computations. He looks at this image below, and finds the structures represented there might be a mistake, based on his considerable experience of these kinds of molecules. I expect he had a gut feeling within seconds of seeing the diagram.

(more…)

Powered by WordPress