Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape.
J Med Chem
; 67(7): 5683-5698, 2024 Apr 11.
Article
em En
| MEDLINE
| ID: mdl-38498697
ABSTRACT
Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against â¼1000 compounds with human absorption data and â¼10,000 AbbVie tool compounds (â¼1000 proteolysis targeting chimeras or PROTACs, â¼7000 Ro5s, and â¼2000 bRo5s) revealed new patterns of physicochemical trends. We introduced a high-throughput "polarity reduction" descriptor ETR, the EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 and PROTAC subsets for specialized drug design strategies for effective absorption. Our methods and guidelines refine drug design by providing innovative in vitro approaches, enhancing physicochemical property optimization, and enabling accurate predictions of intestinal absorption in the complex bRo5 domain.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Descoberta de Drogas
/
Quimera de Direcionamento de Proteólise
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article