title: Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.
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.
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Fader
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Malenfant
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Parisien
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Carson
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bilodeau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Landry
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Pesant
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chabot
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bousquet
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Kawai
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: LaPlante
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Araz
authors.initials: A
authors.lastname: Jakalian
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Punit K
authors.initials: PK
authors.lastname: Bhardwaj
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wernic
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroeder
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Ma'an
authors.initials: M
authors.lastname: Amad
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Edwards
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Cordingley
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Bethell
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Mason
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Poupart
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faucher
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Craig
authors.initials: C
authors.lastname: Fenwick
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Yoakim
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Youla
authors.initials: Y
authors.lastname: Tsantrizos
keywords: HIV Integrase; LTR DNA 3′-processing; NCINI; allosteric inhibitor