Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2

[tetano]

ACS Med Chem Lett. 2017 Jan 20;8(2):256-260. doi: 10.1021/acsmedchemlett.6b00486. eCollection 2017.
[h=1]Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2.[/h] Farmer LJ[SUP]1[/SUP], Clark MP[SUP]1[/SUP], Boyd MJ[SUP]1[/SUP], Perola E[SUP]1[/SUP], Jones SM[SUP]1[/SUP], Tsai A[SUP]1[/SUP], Jacobs MD[SUP]1[/SUP], Bandarage UK[SUP]1[/SUP], Ledeboer MW[SUP]1[/SUP], Wang T[SUP]1[/SUP], Deng H[SUP]1[/SUP], Ledford B[SUP]1[/SUP], Gu W[SUP]1[/SUP], Duffy JP[SUP]1[/SUP], Bethiel RS[SUP]1[/SUP], Shannon D[SUP]1[/SUP], Byrn RA[SUP]1[/SUP], Leeman JR[SUP]1[/SUP], Rijnbrand R[SUP]1[/SUP], Bennett HB[SUP]1[/SUP], O'Brien C[SUP]1[/SUP], Memmott C[SUP]1[/SUP], Nti-Addae K[SUP]1[/SUP], Bennani YL[SUP]1[/SUP], Charifson PS[SUP]1[/SUP].
[h=3]Author information[/h]

[h=3]Abstract[/h] In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.


[h=4]KEYWORDS:[/h] PB2 inhibitor; azaindole; influenza

PMID: 28197322 PMCID: PMC5304291 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00486
[PubMed]