Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles.
J Med Chem
; 56(3): 1124-35, 2013 Feb 14.
Article
em En
| MEDLINE
| ID: mdl-23316884
ABSTRACT
This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridonas
/
Inibidores de Integrase de HIV
/
Integrase de HIV
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article