N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides: Identification of novel orthopoxvirus egress inhibitors.
A series of novel, potent orthopoxvirus egress inhibitors was identified during high-throughput screening of the ViroPharma small molecule collection. Using structure--activity relationship information inferred from early hits, several compounds were synthesized, and compound 14 was identified as a potent, orally bioavailable first-in-class inhibitor of orthopoxvirus egress from infected cells. Compound 14 has shown comparable efficaciousness in three murine orthopoxvirus models and has entered Phase I clinical trials.
Bailey
Thomas R
TR
ViroPharma Incorporated, 397 Eagleview Boulevard, Exton, Pennsylvania 19341, USA. tbailey@cephalon.com
Rippin
Susan R
SR
Opsitnick
Elizabeth
E
Burns
Christopher J
CJ
Pevear
Daniel C
DC
Collett
Marc S
MS
Rhodes
Gerry
G
Tohan
Sanjeev
S
Huggins
John W
JW
Baker
Robert O
RO
Kern
Earl R
ER
Keith
Kathy A
KA
Dai
Dongcheng
D
Yang
Guang
G
Hruby
Dennis
D
Jordan
Robert
R
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D054833:Isoindoles; D008252:Macaca fascicularis; D051379:Mice; D015394:Molecular Structure; D018155:Orthopoxvirus / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D010797:Phthalimides
D000998:Antiviral Agents; D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides