Discovery of ANA975: an oral prodrug of the TLR-7 agonist isatoribine.
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.
Xiang
Alan X
AX
Anadys Pharmaceuticals, Inc., San Diego, California 92121, USA. axiang@anadyspharma.com
Webber
Stephen E
SE
Kerr
Bradley M
BM
Rueden
Erik J
EJ
Lennox
Joseph R
JR
Haley
Gregory J
GJ
Wang
Tingmin
T
Ng
John S
JS
Herbert
Mark R
MR
Clark
David L
DL
Banh
Virginia N
VN
Li
Wei
W
Fletcher
Simon P
SP
Steffy
Kevin R
KR
Bartkowski
Darian M
DM
Kirkovsky
Leonid I
LI
Bauman
Lisa A
LA
Averett
Devron R
DR
D000284:Administration, Oral; D000998:Antiviral Agents / Q000494:pharmacology; D015195:Drug Design; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051199:Toll-Like Receptor 7 / Q000819:agonists*
D000998:Antiviral Agents; D011355:Prodrugs; D011744:Pyrimidinones; D051199:Toll-Like Receptor 7; D006151:Guanosine; C061136:isatoribine