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

Details

Serval ID
serval:BIB_F1EE56BC58BC
Type
Article: article from journal or magazin.
Collection
Publications
Title
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
Journal
ACS medicinal chemistry letters
Author(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
Publication state
Published
Issued date
10/04/2014
Peer-reviewed
Oui
Volume
5
Number
4
Pages
422-427
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
HIV Integrase, LTR DNA 3′-processing, NCINI, allosteric inhibitor
Pubmed
Web of science
Create date
27/08/2024 11:31
Last modification date
05/09/2024 10:01
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