Derek Lowe has a recent post entitled “Another Funny-Looking Structure Comes Through“. He cites a recent medchem article 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. So I pose the question here; why?
- 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-p K a Polar Moiety ", ACS Med. Chem. Lett., vol. 6, pp. 1241-1246, 2015. http://dx.doi.org/10.1021/acsmedchemlett.5b00398