TARGETING AN HIV-1 NEF-HOST CELL KINASE COMPLEX
Drug candidates for inhibition of HIV-1 replication can target Src family kinases (SFK), such as Hck, that interact with Nef protein of the virus. Compounds characterized by such inhibitory activity were identified via an assay for kinase activity of an SFK in a Nef:SFK complex. Illustrative of inhibitors identified using the kinase assay are various 2,3-diaminoquinaxolines and furo[2,3-d]pyrimidines. The inventive inhibitors were found to arrest HIV-1 viral replication in vitro.
1 - 13 . (canceled)
14 . A compound of Formula I,
wherein:
Cy 1 and Cy 2 are independently selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl;
R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, —OR 11 , —SR 11 , —NR 12 R 13 , —C(Z)NR 12 R 13 , and —C(Z)R 14 ;
R 11 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
R 12 and R 13 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or
R 12 and R 13 combine to form a mono-carbocyclic or mono-heterocyclic 5- or 6-membered ring system;
R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and
Z is O or S.
15 . The compound of claim 14 , wherein Cy 1 is aryl optionally substituted with one or more members selected from the group consisting of —OH, halogen, sulfonic acid, nitro, X—CH 2 —C(O)— and —O-alkyl;
Cy 2 is an aryl optionally substituted with one or more members selected from the group consisting of halogen, alkyl, amino and —O-alkyl;
R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen and —OR 11 ;
R 11 is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and
X is a halogen.
16 . The compound of claim 15 , wherein Cy 1 is a naphthyl group and Cy 2 is a 4-chlorophenyl group.
17 . The compound according to claim 15 , wherein Cy 1 is selected from the group consisting of
and
X is a halogen.
18 . The compound according to claim 17 , wherein X is chlorine.
19 . The compound according to claim 15 , wherein said compound is selected from the group consisting of
20 . A compound of Formula III,
wherein:
Cy 3 and Cy 4 are independently selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R 2 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl; and
R 20 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl.
21 . The compound of claim 20 , wherein R 2 is hydrogen and when Cy 3 and Cy 4 are each independently aryl or heteroaryl, the aryl and heteroaryl groups are each optionally substituted with one or more members selected from the group consisting of —OH, alkyl and alkoxy.
22 . The compound of claim 20 , wherein R 20 is an alkyl substituted with one or more members selected from the group consisting of —OH, heteroaryl, —NH 2 , and —COOH.
23 . The compound of claim 21 , wherein Cy 3 and Cy 4 are each independently selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl and furan.
24 . The compound of claim 20 , wherein R 20 is selected from the group consisting of methyl, ethyl, propyl, and butyl.
25 . The compound of claim 20 , wherein R 20 is an optionally substituted heteroarylalkyl selected from the group consisting of 2-methylfuran, N-ethyl morpholine, N-propyl morpholine, and furan-2-carboxylate.
26 . A compound selected from the following table:
27 . The compound of claim 26 , wherein the compound is
28 . A method for treating HIV-1 in a subject in need thereof, comprising:
(a) identifying a subject infected with HIV-1 and then (b) administering to the subject a therapeutic dose of a Formula III compound
wherein:
Cy 3 and Cy 4 are independently selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R 2 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl; and
R 20 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl.
29 . The method according claim 28 , wherein the compound is selected from the group consisting of
30 . The method according claim 29 , wherein the compound is