Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 protein-protein interaction: a combined medicinal chemistry, NMR and computational chemistry approach.
We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1-E2 protein-protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.
Goudreau
Nathalie
N
Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Que., Canada H7S 2G5. ngoudreau@lav.boehringer-ingelheim.com
Cameron
Dale R
DR
Déziel
Robert
R
Haché
Bruno
B
Jakalian
Araz
A
Malenfant
Eric
E
Naud
Julie
J
Ogilvie
William W
WW
O'meara
Jeff
J
White
Peter W
PW
Yoakim
Christiane
C
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000737:chemistry; D052140:Human papillomavirus 11 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; C084304:E1 protein, Human papillomavirus type 11; C117355:E2 protein, Human papillomavirus type 11; D004852:Epoxy Compounds; D007202:Indicators and Reagents; D014764:Viral Proteins