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Macrocycles, the edge of drug‐likeness chemical space or Goldilocks zone?
Author(s) -
Selwood David L.
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12922
Subject(s) - saquinavir , verteporfin , lipinski's rule of five , chemical space , chemistry , pharmacology , medicine , drug discovery , computer science , human immunodeficiency virus (hiv) , nanotechnology , antiretroviral therapy , surgery , virology , materials science , biochemistry , visual acuity , choroidal neovascularization , viral load , in silico , gene
Some glass ceilings are waiting to be broken. If you are a follower of Chris Lipinski’s rules,[1] then you should probably stop reading: any commentary about macrocyclic drugs is likely to induce nausea, dizziness and disbelief in devotees. The rules were of course derived from a data set of known orally bioavailable drugs and represent a snapshot in time: data set selection is everything in this field and is the elephant in the room. Empirically derived rules are tautologies and we should not be surprised when they are broken once we step outside of the data set.[2] The most fragile part of this particular glass ceiling is the molecular weight limit of 500 Da, a limit easily smashed by modern blockbuster drugs and some older former blockbuster macrocycles such as cyclosporin 1 (Figure 1). As medicinal chemistry has developed and encompassed protein–protein interaction targets, so the size of molecules has increased over time leading to the beyond Ro5 or bRo5 concept.[3] This trend was first evident with the HIV protease inhibitors such as saquinavir 2, but continues to the present day with the new BCl2 inhibitor ABT199, venetoclax 3, the HCV drug velpatasvir 4 and many other natural product examples (Figure 1). Verteporfin 5 (Figure 2) is a photodynamic therapy drug delivered intravenously for the treatment of AMD in