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ACS Med Chem Lett. 2017 Jan 20;8(2):256-260. doi: 10.1021/acsmedchemlett.6b00486. eCollection 2017.
Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2.
Farmer LJ1, Clark MP1, Boyd MJ1, Perola E1, Jones SM1, Tsai A1, Jacobs MD1, Bandarage UK1, Ledeboer MW1, Wang T1, Deng H1, Ledford B1, Gu W1, Duffy JP1, Bethiel RS1, Shannon D1, Byrn RA1, Leeman JR1, Rijnbrand R1, Bennett HB1, O'Brien C1, Memmott C1, Nti-Addae K1, Bennani YL1, Charifson PS1.
Author information
Abstract
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.
KEYWORDS:
PB2 inhibitor; azaindole; influenza
PMID: 28197322 PMCID: PMC5304291 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00486
[PubMed]
Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2.
Farmer LJ1, Clark MP1, Boyd MJ1, Perola E1, Jones SM1, Tsai A1, Jacobs MD1, Bandarage UK1, Ledeboer MW1, Wang T1, Deng H1, Ledford B1, Gu W1, Duffy JP1, Bethiel RS1, Shannon D1, Byrn RA1, Leeman JR1, Rijnbrand R1, Bennett HB1, O'Brien C1, Memmott C1, Nti-Addae K1, Bennani YL1, Charifson PS1.
Author information
Abstract
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.
KEYWORDS:
PB2 inhibitor; azaindole; influenza
PMID: 28197322 PMCID: PMC5304291 [Available on 2018-02-09] DOI: 10.1021/acsmedchemlett.6b00486
[PubMed]