Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs.
Drug Discov Today
; 21(5): 712-7, 2016 05.
Article
em En
| MEDLINE
| ID: mdl-26891978
ABSTRACT
Key to the pharmaceutical utility of certain macrocyclic drugs is a 'chameleonic' ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes. Based on analysis of the structures of 20 macrocyclic compounds that are approved oral drugs, we propose that good solubility requires a topological polar surface area (TPSA, in Å(2)) of ≥0.2×molecular weight (MW). Meanwhile, good passive membrane permeability requires a molecular (i.e., 3D) PSA in nonpolar environments of ≤140Å(2). We show that one or other of these limits is almost invariably violated for compounds with MW>600Da, suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Compostos Macrocíclicos
Limite:
Humans
Idioma:
En
Revista:
Drug Discov Today
Assunto da revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Ano de publicação:
2016
Tipo de documento:
Article