Inhibitors of short-chain dehydrogenase activity for modulating hematopoietic stem cells and hematopoiesis

A method increasing numbers of and/or of mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V):

• wherein n is 0-2
• X6 is independently is N or CRc
• R1, R6, R7, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl;
• U1 is N, C—R2, or C—NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X, X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′)2, O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′)2, COOR′ (wherein R′ is H or a lower alkyl group), and R3 or R4 may be absent;
• and pharmaceutically acceptable salts thereof;
• and
• wherein the subject has received a hematopoietic stem cell transplant or a bone marrow transplant.

A method of treating at least one of neutropenia, thrombocytopenia, anemia, or cytopenia in a subject in need thereof, the method comprising:

• administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V):
• wherein n is 0-2
• X6 is independently is N or CRc
• R1, R6, R7, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl;
• U1 is N, C—R2, or C—NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X, X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′)2, O(CO)R′, COOR′ (wherein R′ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(R′)2, COOR′ (wherein R′ is H or a lower alkyl group), and R3 or R4 may be absent;
• and pharmaceutically acceptable salts thereof;
• and
• wherein the subject has received a hematopoietic stem cell transplant or a bone marrow transplant.