Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.

Détails

ID Serval
serval:BIB_F1EE56BC58BC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
Périodique
ACS medicinal chemistry letters
Auteur⸱e⸱s
Fader L.D., Malenfant E., Parisien M., Carson R., Bilodeau F., Landry S., Pesant M., Brochu C., Morin S., Chabot C., Halmos T., Bousquet Y., Bailey M.D., Kawai S.H., Coulombe R., LaPlante S., Jakalian A., Bhardwaj P.K., Wernic D., Schroeder P., Amad M., Edwards P., Garneau M., Duan J., Cordingley M., Bethell R., Mason S.W., Bös M., Bonneau P., Poupart M.A., Faucher A.M., Simoneau B., Fenwick C., Yoakim C., Tsantrizos Y.
ISSN
1948-5875 (Print)
ISSN-L
1948-5875
Statut éditorial
Publié
Date de publication
10/04/2014
Peer-reviewed
Oui
Volume
5
Numéro
4
Pages
422-427
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.
Mots-clé
HIV Integrase, LTR DNA 3′-processing, NCINI, allosteric inhibitor
Pubmed
Web of science
Création de la notice
27/08/2024 10:31
Dernière modification de la notice
05/09/2024 9:01
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