Small molecule antiviral drug treatment for human papillomavirus infections
Compositions and methods are provided for treating HPV infections including pre-malignant and cancers. Compounds that specifically bind to the HPV E6 protein and inactivate the protein are disclosed.
1 . A compound of formula Ib:
wherein:
R 1a and R 1b are independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with R D ;
R 3 is independently C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, —NH(R A ), or —N(R A )(R B ), wherein each hydrogen atom in C6-C10 aryl is optionally substituted by R D , and wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with a C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with at least one R D ;
R A and R B are independently C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is optionally substituted with R D ;
each R D is independently deuterium, halogen, C1-C6 alkyl, or —OC1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with deuterium, halogen, or oxo;
R C is C3-C8 heterocycloalkyl-R E or —C1-C6 alkyl-C3-C8 heterocycloalkyl-R E , wherein each hydrogen atom in the C3-C8 heterocycloalkyl is optionally substituted with C1-C6 alkyl, oxo, or C3-C8 heterocycloalkyl; and
R E is
wherein:
X 3 is CH or N;
R 60 is H or F; and
R 65 and R 66 are each methyl or together with the atom to which they are attached form a 4, 5 or 6-membered cycloalkyl or heterocycloalkyl ring,
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 3 is C1-C6 alkyl.
3 . The compound of claim 2 , wherein the C1-C6 alkyl is substituted by C6-C10 aryl, optionally substituted with at least one R D .
4 . The compound of claim 1 , wherein R 3 is C3-C6 cycloalkyl.
5 . The compound of claim 1 , wherein R 3 is-N(R A ) (R B ), R A is H or methyl, and R B is benzyl, optionally substituted with fluorine.
6 . The compound of claim 1 , wherein R C is C3-C8 heterocycloalkyl-R E .
7 . The compound of claim 6 , wherein R C is-piperazine-R E .
8 . A formulation comprising:
(a) an effective amount of a compound of formula Ib for treating human papillomavirus (HPV) infection:
wherein:
R 1a and R 1b are independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with R D ;
R 3 is independently H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, —NH(R A ), or —N(R A ) (R B ), wherein each hydrogen atom in C6-C10 aryl is optionally substituted by R D , and wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with a C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with at least one R D ;
R A and R B are independently C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with C6-C10 aryl, wherein each hydrogen atom in C6-C10 aryl is optionally substituted with R D ;
each R D is independently deuterium, halogen, C1-C6 alkyl, or —OC1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted with deuterium, halogen, or oxo;
R C is C3-C8 heterocycloalkyl-R E or —C1-C6 alkyl-C3-C8 heterocycloalkyl-R E , wherein each hydrogen atom in the C3-C8 heterocycloalkyl is optionally substituted with C1-C6 alkyl, oxo, or C3-C8 heterocycloalkyl; and
R E is
wherein:
X 3 is CH or N;
R 60 is H or F; and
R 65 and R 66 are each methyl or together with the atom to which they are attached form a 4, 5 or 6-membered cycloalkyl or heterocycloalkyl ring,
or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable adjuvant, diluent or carrier.
9 . The formulation of claim 8 , provided in a nanoparticle for targeted delivery.
10 . The formulation of claim 8 , wherein the formulation is formulated to be delivered orally, transdermally, topically, subcutaneously, intramuscularly, or intravenously.
11 . The formulation of claim 8 , wherein the formulation is formulated for topical application to the cervix, anus, or oropharynx.
12 . A method for treating an HPV infection, the method comprising administering the formulation of claim 8 to a subject in need of treating the HPV infection.
13 . The method of claim 12 , wherein the compound inhibits E6AP binding to HPV E6 preventing ubiquitination of p53.
14 . The compound of claim 1 , wherein R 1a and R 1b are H.
15 . The compound of claim 1 , wherein R 3 is C6-C10 aryl.
16 . The compound of claim 15 , wherein R 3 is phenyl.
17 . The compound of claim 15 , wherein at least one hydrogen atom in the C6-C10 aryl is substituted by R D .
18 . The compound of claim 8 wherein R C is C3-C8 heterocycloalkyl-R E , and R 1a and R 1b are each H.
19 . The compounds of claim 8 wherein R C is C3-C8 heterocycloalkyl-R E , and R 3 is C6-C10 aryl.