tetano
Editor, Senior Moderator
ACS Med Chem Lett. 2017 Jan 18;8(2):261-265. doi: 10.1021/acsmedchemlett.6b00487. eCollection 2017.
[h=1]Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.[/h] Bandarage UK[SUP]1[/SUP], Clark MP[SUP]1[/SUP], Perola E[SUP]1[/SUP], Gao H[SUP]1[/SUP], Jacobs MD[SUP]1[/SUP], Tsai A[SUP]1[/SUP], Gillespie J[SUP]1[/SUP], Kennedy JM[SUP]1[/SUP], Maltais F[SUP]1[/SUP], Ledeboer MW[SUP]1[/SUP], Davies I[SUP]1[/SUP], Gu W[SUP]1[/SUP], Byrn RA[SUP]1[/SUP], Nti Addae K[SUP]1[/SUP], Bennett H[SUP]1[/SUP], Leeman JR[SUP]1[/SUP], Jones SM[SUP]1[/SUP], O'Brien C[SUP]1[/SUP], Memmott C[SUP]1[/SUP], Bennani Y[SUP]1[/SUP], Charifson PS[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] 7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability
PMID: 28197323 PMCID: PMC5304303 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00487
[PubMed]
[h=1]Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.[/h] Bandarage UK[SUP]1[/SUP], Clark MP[SUP]1[/SUP], Perola E[SUP]1[/SUP], Gao H[SUP]1[/SUP], Jacobs MD[SUP]1[/SUP], Tsai A[SUP]1[/SUP], Gillespie J[SUP]1[/SUP], Kennedy JM[SUP]1[/SUP], Maltais F[SUP]1[/SUP], Ledeboer MW[SUP]1[/SUP], Davies I[SUP]1[/SUP], Gu W[SUP]1[/SUP], Byrn RA[SUP]1[/SUP], Nti Addae K[SUP]1[/SUP], Bennett H[SUP]1[/SUP], Leeman JR[SUP]1[/SUP], Jones SM[SUP]1[/SUP], O'Brien C[SUP]1[/SUP], Memmott C[SUP]1[/SUP], Bennani Y[SUP]1[/SUP], Charifson PS[SUP]1[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] 7-azaindole; Influenza; PB2 subunit; aldehyde oxidase; metabolic stability
PMID: 28197323 PMCID: PMC5304303 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00487
[PubMed]