title: Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.
abstract: JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clark
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Huai
authors.initials: H
authors.lastname: Gao
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jacobs
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Tsai
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Gillespie
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Kennedy
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: François
authors.initials: F
authors.lastname: Maltais
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Ioana
authors.initials: I
authors.lastname: Davies
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kwame
authors.initials: K
authors.lastname: Nti Addae
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Hamilton
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Leeman
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Colleen
authors.initials: C
authors.lastname: O'Brien
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Memmott
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
keywords: 7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability