Compositions and methods for inhibiting proteases
In particular, in alternative embodiments, the invention provides pharmaceutical compounds and formulations comprising a family of epoxyketone compounds, which include racemic mixtures or racemates, isomers, stereoisomers, diastereoisomers, derivatives and analogs, and methods for making and using them. In alternative embodiments, pharmaceutical compositions and formulations of the invention are administered to an individual in need thereof in an amount sufficient to treat, prevent, reverse and/or ameliorate an infection, disease or condition that can be ameliorated, treated, prevented or reversed by partially or completely inhibiting a chymotrypsin-like protease or a proteasome activity, including e.g., a retroviral infection such as human immunodeficiency virus-1 (HIV-1) infection, an immune disorder, a neurodegenerative disease or condition, or a cancer such as a myeloma or multiple myeloma, an adenocarcinoma such as a lung adenocarcinoma, a pancreatic cancer, a B-cell related cancer, and lymphomas such as non-Hodgkin's lymphoma.
1. A composition, a pharmaceutical composition or a formulation comprising a compound selected from the group consisting of:
(i) a compound having the formula:
wherein X is selected from the group consisting of H, OH, OR, an alkyl group, an alkene group, an aromatic group, NH 2 , NHR, and NR 2 , wherein R is independently selected from the group consisting of an isopropyl group, an alkyl group, an alkene, an aryl group and an aromatic group,
wherein A is selected from the group consisting of O, NH and S,
wherein Y is selected from the group consisting of O, NH, S, SH, SCH 3 , (SO 2 )CH 3 , H, OH, OR, an alkyl group, an alkene group, an isopropyl group, an aryl group, an aromatic group, NH 2 , NHR, and NR 2 , wherein R is independently selected from the group consisting of an isopropyl group, an alkyl group, an alkene, an aryl group and an aromatic group,
wherein B is selected from the group consisting of S═O (sulfoxide) or S(═O) 2 (sulfone), and optionally the S (sulfur atom) has different oxidation states
(ii) a racemic mixture or a racemate, an isomer, a stereoisomer, a diastereoisomer, of a compound of (i);
(iii) the compound of (i) or (ii), wherein any one, several or all of the methyl groups are independently substituted with any alky, alkene, phenoxy or alkoxy group; or, any one, several or all of the methyl groups are independently substituted with a hydrogen, halo, hydroxy (—OH), phenoxy, thiol (—SH), cyano (—CN), formyl (—CHO), alkyl, haloalkyl, alkene, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, substituted aryl, amino, nitro (—NO 2 ), alkoxy, haloalkoxy, thioalkoxy, alkanoyl, haloalkanoyl and/or carbonyloxy group;
(iv) the compound of any of (i) to (iii), wherein any one, several or all of the hydrogen groups are independently substituted with a fluorine or a deuterium;
(v) any combination of any of (i) to (iv), or optionally any one or combination of (i) to (iv) comprising a pharmaceutically acceptable buffer, diluent, stabilizing agent and/or carrier; and
(vi) a pharmaceutically acceptable salt of any of (i) to (v).
2. The compound of claim 1 , formulated as a pharmaceutical composition for enteral or parenteral administration.
3. The compound of claim 1 , wherein the compound has four stereocenters.
4. A formulation or a pharmaceutical composition comprising a compound or composition of claim 1 .
5. The formulation or a pharmaceutical composition of claim 4 , wherein the compound is formulated for administration in vivo; or for enteral or parenteral administration, or as a tablet, pill, capsule, gel, geltab, liquid, lotion, aerosol or implant.
6. The compound of claim 1 , wherein the compound has the formula:
wherein R is selected from the group consisting of S═O (sulfoxide) or S(═O) 2 (sulfone), and optionally the S (sulfur atom) has different oxidation states.
7. The compound of claim 1 , wherein any one, several or all of the methyl groups are independently substituted with any alky, alkene, phenoxy or alkoxy group.
8. The compound of claim 1 , wherein any one, several or all of the methyl groups are independently substituted with a hydrogen, a halo, a hydroxy (—OH), a phenoxy, thiol (—SH), a cyano (—CN), a formyl (—CHO), an alkyl, a haloalkyl, an alkene, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkenyl, a heteroalkynyl, an aryl, a substituted aryl, an amino, a nitro (—NO 2 ), an alkoxy, a haloalkoxy, a thioalkoxy, an alkanoyl, a haloalkanoyl and/or a carbonyloxy group.
9. The compound of claim 1 , wherein any one, several or all of the hydrogen groups are independently substituted with a fluorine or a deuterium.