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ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487. eCollection 2017.
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.
Bandarage UK1, Clark MP1, Perola E1, Gao H1, Jacobs MD1, Tsai A1, Gillespie J1, Kennedy JM1, Maltais F1, Ledeboer MW1, Davies I1, Gu W1, Byrn RA1, Nti Addae K1, Bennett H1, Leeman JR1, Jones SM1, O'Brien C1, Memmott C1, Bennani Y1, Charifson PS1.
Author information
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.
KEYWORDS:
7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability
PMID: 28197323 PMCID: PMC5304303 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00487
[PubMed]
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.
Bandarage UK1, Clark MP1, Perola E1, Gao H1, Jacobs MD1, Tsai A1, Gillespie J1, Kennedy JM1, Maltais F1, Ledeboer MW1, Davies I1, Gu W1, Byrn RA1, Nti Addae K1, Bennett H1, Leeman JR1, Jones SM1, O'Brien C1, Memmott C1, Bennani Y1, Charifson PS1.
Author information
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.
KEYWORDS:
7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability
PMID: 28197323 PMCID: PMC5304303 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00487
[PubMed]