An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
Watson
Keith G
KG
Biota Chemistry Laboratory, School of Chemistry, Monash University, PO Box 23 Victoria, Australia 3800. kwatson@wehi.edu.au
Brown
Renee N
RN
Cameron
Rachel
R
Chalmers
David K
DK
Hamilton
Stephanie
S
Jin
Betty
B
Krippner
Guy Y
GY
Luttick
Angela
A
McConnell
Darryl B
DB
Reece
Phillip A
PA
Ryan
Jane
J
Stanislawski
Pauline C
PC
Tucker
Simon P
SP
Wu
Wen-Yang
WY
Barnard
Dale L
DL
Sidwell
Robert W
RW
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002213:Capsid / Q000378:metabolism*; D002460:Cell Line; D004987:Ethers; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011724:Pyridazines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D004987:Ethers; D010091:Oximes; D010880:Piperidines; D011724:Pyridazines; C074589:pirodavir