METHODS FOR MODULATING BONE FORMATION AND MINERALIZATION
Methods and compositions for modulating bone formation and mineralization are described.
1 . A method for modulating bone formation and mineralization, comprising administering to a subject an effective amount of a Shn3 modulating compound, such that bone formation and mineralization is modulated.
2 . The method of claim 1 , wherein said compound modulates Shn3 and WWP1 association.
3 . The method of claim 2 , wherein said compound inhibits Shn3 and WWP1 association.
4 . The method of claim 1 , wherein said compound binds to WWP1.
5 . The method of claim 1 , wherein said compound binds to Runx2.
6 . The method of claim 1 , wherein said compound prevents the ubiquination of Runx2.
7 . The method of claim 1 , wherein said compound increases bone formation and mineralization.
8 . The method of claim 1 , wherein said effective amount is effective to treat osteoporosis.
9 . The method of claim 1 , wherein said effective amount is effective to treat osteolytic metastases.
10 . The method of claim 1 , wherein said compound is of formula (I):
wherein:
L is a linking moiety:
P 1 and P 2 are each independently selected optionally substituted cyclic moieties;
a and b are each independently a single or double bond; and pharmaceutically acceptable salts thereof.
11 . The method of claim 10 , wherein said linking moiety is:
—(CR 1 R 2 ) 0-10 -G-(CR 3 R 4 ) 0-10 —
wherein:
G is carbonyl, —SO 2 —, —O—, —S—, —PO 3 —, (NR 5 ) 1-2 , a ring moiety, or absent;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano or absent.
12 . The method of claim 11 , wherein said linking moiety is:
—(CH 2 ) 0-2 —SO 2 —(CH 2 ) 0-2 —.
13 . The method of claim 12 , wherein said linking moiety comprises one or more nitrogen atoms.
14 . The method of claim 13 , wherein said linking moiety is ═N—N═CH—.
15 . The method of claim 10 , wherein said linking moiety is a cyclic moiety.
16 . The method of claim 15 , wherein said cyclic moiety is a heterocycle.
17 . The method of claim 16 , wherein said cyclic moiety is:
wherein
R 6 is hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, or alkoxy.
18 . The method of claim 10 , wherein each of P 1 and P 2 is an independently selected pyrimidine base or derivative thereof.
19 . The method of claim 18 , wherein each of P 1 and P 2 are each independently uracil or a derivative thereof.
20 . The method of claim 19 , wherein said compound is:
21 . The method of claim 10 , wherein P 1 and P 2 are each independently selected carbocycles.
22 . The method of claim 21 , wherein at least one of P 1 and P 2 is aromatic.
23 . The method of claim 22 , wherein at least one of P 1 and P 2 is substituted or unsubstituted phenyl.
24 . The method of claim 21 , wherein at least one of P 1 and P 2 is polycyclic.
25 . The method of claim 24 , wherein at least one of P 1 and P 2 is substituted or unsubstituted fluorene.
26 . The method of claim 25 , wherein said compound is:
27 . The method of claim 10 , wherein P 1 is carbocyclic and P 2 is heterocyclic.
28 . The method of claim 27 , wherein P 1 is aromatic.
29 . The method of claim 28 , wherein P 1 is substituted or unsubstituted phenyl.
30 . The method of claim 27 , wherein P 2 comprises one or more oxygen atoms.
31 . The method of claim 27 , wherein P 2 comprises one of more carbonyl groups.
32 . The method of claim 27 , wherein said compound is:
33 . A method for treating osteoporosis, comprising administering to a subject an effective amount of a compound of formula (I), such that said subject is treated for osteoporosis, wherein said compound of formula (I) is:
wherein:
L is a linking moiety:
P 1 and P 2 are each independently selected optionally substituted cyclic moieties;
a and b are each independently a single or double bond; or a pharmaceutically acceptable salt, ester or prodrug thereof.
34 . The method of claim 33 , wherein said compound of formula (I) enhances osteoblast synthesis.
35 . A method for treating osteoporosis, comprising administering to a subject an effective amount of a compound orally, such that said subject is treated.
36 . The method of claim 35 , wherein said compound is a compound of formula (I)
wherein:
L is a linking moiety:
P 1 and P 2 are each independently selected optionally substituted cyclic moieties;
a and b are each independently a single or double bond; or a pharmaceutically acceptable salt, ester or prodrug thereof.
37 . The method of claim 35 , wherein said compound enhances osteoblast synthetic activity.
38 . The method of claim 35 , wherein said compound enhances bone growth.
39 . The method of claim 1 , wherein said subject is suffering from osteoporosis or osteolytic metastases.
40 . The method of claim 1 , wherein said subject is at risk of suffering from osteoporosis.
41 . The method of claim 1 , wherein said subject is female.
42 . The method of claim 1 , wherein said subject is over 40 years of age.
43 . The method of claim 42 , wherein said subject is over 50 years of age.
44 . The method of claim 43 , wherein said subject is over 60 years of age.
45 . The method of claim 44 , wherein said subject is over 70 years of age.
46 . The method of claim 45 , wherein said subject is over 80 years of age.
47 . The method of claim 1 , wherein said subject is human.
48 . A pharmaceutical composition comprising an orally effective amount of a compound for enhancing osteoblast synthesis and a pharmaceutically acceptable carrier.
49 . The pharmaceutical composition of claim 48 , wherein said compound is a compound of formula (I):
wherein:
L is a linking moiety:
P 1 and P 2 are each independently selected optionally substituted cyclic moieties;
a and b are each independently a single or double bond; and pharmaceutically acceptable salts thereof.
50 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I):
wherein:
L is a linking moiety:
P 1 and P 2 are each independently selected optionally substituted cyclic moieties;
a and b are each independently a single or double bond; and pharmaceutically acceptable salts thereof.
51 . The pharmaceutical composition of claim 50 , wherein said effective amount is effective to modulate bone formation or mineralization.
52 . A pharmaceutical composition, comprising an effective amount of a Shn3 modulating compound and a pharmaceutically acceptable carrier.
53 . A compound of formula (IIa):
Q 1 -L 1 -Q 2 (IIa)
wherein:
L′ is a linking moiety;
Q 1 is an optionally substituted heterocyclic moiety comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups;
Q 2 is an optionally substituted aryl, heteroaryl, polycyclic, alkyl, alkenyl, or a heterocyclic moiety, optionally comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, provided that said compound is not 5,5′-(sulfonyldimethylene)diuracil; 5,5′-(thiodimethylene)di-uracil; 5,5′-(dithiodimethylene)diuracil; 5,5′-[dioxybis(methylene)]bis-2,4[1H, 3H]-pyrimidone; 5-phenyl[(phenylmethyl)sulfonyl]methyl]-2,4(1H,3H)-pyrimidinedione; 5,5′-(oxydimethylene)bis[2-methyl-4,6-pyrimidinediol; 5-[(methylsulfinyl)methyl]-2,4(1H,3H)-pyrimidinedione; 5-[phenyl[(phenylmethyl)sulfinyl]methyl]-2,4(1H,3H-pyrimidinedione; 5-[[(phenylmethyl)thio]methyl]-2,4(1H,3H)-pyrimidinedione; 5-[(2-pyrimidinylthio)methyl]-2,4(1H,3H)-pyrimidinedione; 5,5′-ethylenediuracil; S-[(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinyl)methyl]benzenecarbothioic acid ester; 5-[(benzylsulfonyl)methyl]-5-ethyl-barbituric acid; 5-ethylthiomethyluracil; 5,6-bis[(methylsulfonyl)methyl]-2,4(1H, 3H)-pyrimidinedione; 5,5′-(thiodi-2,1-ethanediyl)bis[6-methyl])-2,4 (1H,3H-pyrimidinedione; 5,5′-methylene diuracil; 5,5′-pentylidenebis-2,4 (1H,3H)-pyrimidinedione; 5,5′-(3-methyl-1-propene-1,2-diyl)bis 2,4 (1H,3′-pyrimidinedione; 2,2′-dithiobis[5-methyl-]-4,6-pyrimidinediol; or 2-methyl-5[(phenylsulfonyl)methyl]-4(1H)-pyrimidinone.
54 . The compound of claim 53 , wherein Q 1 is:
wherein:
c is a single or double bond;
X 1 and X 2 are each independently oxygen or sulfur;
Y 1 and Y 1 are each independently oxygen, sulfur, nitrogen or carbon;
R 7 , R 7′ , R 8 , R 8′ , R 9 , and R 9′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, nitro, cyano, thiol, amino, acyl, or absent, or a tautomer thereof, provided that when Y 1 is oxygen or sulfur, R 8 and R 8′ are absent; when Y 1 is nitrogen, R 8′ is absent; when Y 2 is oxygen or sulfur, R 9 and R 9′ are absent; when Y 2 is nitrogen, R 9′ is absent.
55 . A compound of formula (IIb):
wherein:
c and d are independently selected single or double bonds;
L 1 is a linking moiety;
X 1 , X 2 , X 3 , and X 4 are each independently oxygen or sulfur;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently oxygen, sulfur, nitrogen or carbon;
R 7 , R 7′ , R 8 , R 8′ , R 9 , R 9′ , R 10 , R 10′ , R 11 , R 11′ , R 12 , R 12′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, nitro, thiol, amino, acyl, or absent, or a pharmaceutically acceptable salt, ester, prodrug, or tautomer thereof;
provided that: when Y 1 is oxygen or sulfur, R 8 and R 8′ are absent; when Y 1 is nitrogen, R 8′ is absent; when Y 2 is oxygen or sulfur, R 9 and R 9′ are absent; when Y 2 is nitrogen, R 9′ is absent; when Y 3 is oxygen or sulfur, R 11 and R 11′ are absent; when Y 3 is nitrogen, R 11′ is absent; when Y 4 is oxygen or sulfur, R 12 and R 12′ are absent; when Y 4 is nitrogen, R 12′ is absent; when c is a double bond, R 7′ is absent; when d is a double bond, R 10′ is absent; and said compound is not 5,5′-(sulfonyldimethylene)diuracil; 5,5′-(thiodimethylene)di-uracil; 5,5′-(dithiodimethylene)diuracil; 5,5′-[dioxybis(methylene)]bis-2,4-[1H, 3H]-pyrimidone; 5,5′-(oxydimethylene)bis[2-methyl-4,6-pyrimidinediol; 5,6-bis[(methylsulfonyl)methyl]-2,4(1H, 3H)-pyrimidinedione; 5,5′-(thiodi-2,1-ethanediyl)bis[6-methyl])-2,4 (1H,3H)-pyrimidinedione; 5,5′-methylene diuracil; 5,5′-pentylidenebis-2,4 (1H,3H)-pyrimidinedione; or 5,5′-(3-methyl-1-propene-1,2-diyl)bis 2,4 (1H,3H)-pyrimidinedione.
56 . The compound of claim 55 , wherein L 1 is:
(CR 1 R 2 ) 0-10 -(G) 0-2 -(CR 3 R 4 ) 0-10 —
wherein:
G is carbonyl, —SO 2 —, —SO—, —O—, —S—, —PO 3 —, or (NR 5 ) 1-2 ;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, nitro, thiol, hydroxyl, alkoxy, cyano or absent.
57 . The compound of claim 56 , wherein L 1 is:
—(CH 2 ) 0-2 —SO 2 —(CH 2 ) 0-2 —.
58 . The compound of claim 55 , wherein c and d are each double bonds.
59 . The compound of claim 55 , wherein X 1 , X 2 , X 3 , and X 4 are each oxygen.
60 . The compound of claim 55 , wherein Y 1 , Y 2 , Y 3 , and Y 4 are nitrogen.
61 . The compound of claim 55 , wherein R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen.
62 . The compound of claim 55 , wherein said compound is of formula (IIc):
63 . The compound of claim 53 , wherein said compound has no more than five hydrogen bond donors, no more than ten hydrogen bond acceptors, a molecular weight under 500, and a partition coefficient of log P under 5.
64 . A compound of formula (IIIa):
wherein:
X 5 and X 6 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 is oxygen, sulfur, nitrogen, or carbon;
R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, acyl, absent, or K-W;
W is an independently selected optionally substituted aryl, heteroaryl, cyclic or polycyclic group;
K is an independently selecting alkyl, alkenyl, alkynyl, oxo, or amino group;
or a pharmaceutically acceptable salt, tautomer, ester or prodrug thereof;
provided that when Y 5 is nitrogen, R 13′ is absent; when Y 6 is oxygen or sulfur, R 14 and R 14′ are each absent; when Y 6 is carbon, R 14′ is absent; and two of R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ , not covalently bonded to the same atom, are W; and said compound is not 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(4-methoxyphenyl)methylene]-2,4-imidazolidinedione; 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(3-hydroxyphenyl)methylene]-2,4-imidazolidinedione; 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(2-ethoxyphenyl)methylene]-2,4-imidazolidinedione; 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(2-bromophenyl)methylene]-2,4-imidazolidinedione; 3-[[4-[2-methoxyphenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 3-[[4-phenylmethylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 3-[[4-[4-methoxyphenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(4-hydroxy, 3-methoxyphenyl)methylene]-2,4-imidazolidinedione; 3-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-5-[(4-nitrophenyl)methylene]-2,4-imidazolidinedione; 3-[[4-[(4-ethoxyphenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 3-[[4-[(4-nitrophenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 5-[(2-bromophenyl)methylene]-3-[(3,4-dihydro-2,4-dioxo-2H-1-benzopyran-3-yl)methyl]-2,4-imidazolidinedione; 3-[[4-[(3,4-dimethoxyphenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 3-[(3,4-dihydro-2,4-dihydro-2,4-dioxo-2H-1-benzopyran-3-yl)methyl]-5-[(3,4-dimethoxyphenyl)methylene]-2,4-imidazolidinedione; 3-[[4-[(4-acetylaminophenyl)methylene]-5-oxo-2-thioxo-1-imidazolidinyl]methylene]-2H-1-benzopyran-2,4(3H)-dione; 5-[(6-methoxy-1,3-benzodioxol-5-yl)methylene]-3-(phenylmethyl)-2,4-imidazolidinedione; 5-[(6-ethoxy-1,3-benzodioxol-5-yl)methylene]-3-(phenylmethyl)-2,4-imidazolidinedione; 1-[(2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene)methyl]-3-[(2-hydroxyphenyl)methylene]-2,5-pyrrolidinedione; or 5-[(6-ethoxy-1,3-benzodioxol-5-yl)methylene]-3-[(4-methylphenyl)methyl]-2,4-imidazolidinedione.
65 . The compound of claim 64 , wherein Y 5 and Y 6 are each nitrogen.
66 . The compound of claim 64 , wherein R 13 and R 15 are each K-W.
67 . The compound of claim 64 , wherein said compound is a compound of formula (IIIb):
wherein:
e and f are each independently a single or double bond;
W 1 and W 2 are independently selected optionally substituted aryl, heteroaryl, cyclic or polycyclic group;
X 5 and X 6 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 is oxygen, sulfur, nitrogen, or carbon;
R 13 , R 14 , R 14′ , R 15 , R 16 , R 16′ , R 20 and R 20′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, acyl, absent; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
68 . The compound of claim 67 , wherein W 1 is polycyclic.
69 . The compound of claim 68 , wherein W 1 is substituted or unsubstituted 2,4-dioxo-2H-1-benzopyran-3(4H)-ylidene.
70 . The compound of claim 67 , wherein W 2 is substituted or unsubstituted phenyl.
71 . The compound of claim 67 , wherein said compound is of formula (IIIc):
wherein:
e, f, and g are each independently a single or double bond;
M is a substituted or unsubstituted aryl or heteroaryl;
X 5 , X 6 , X 7 and X 8 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 and Y 7 are each independently oxygen, sulfur, nitrogen, or carbon;
R 13 , R 14 , R 14′ , R 15 , R 16 , R 16′ , R 17 , R 17′ , R 18 , R 18′ , R 19 , R 19′ , R 20 and R 20′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, nitro, acyl, absent, or R 17 and R 18 may be linked to form a ring; or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof;
provided that when e is a double bond, R 15 and R 16′ are absent; when f is a double bond, R 20′ is absent; when g is a double bond, R 18′ and R 17′ are absent; when Y 5 is nitrogen, R 13 is absent; when Y 6 is oxygen or sulfur, R 14 and R 14′ are each absent; when Y 6 is carbon, R 14′ is absent; when Y 7 is oxygen or sulfur, R 19 and R 19′ are each absent; when Y 7 is carbon, R 19′ is absent.
72 . The compound of claim 71 , wherein each of e, f, and g are double bonds.
73 . The compound of claim 71 , wherein M is substituted aryl.
74 . The compound of claim 73 , wherein M is substituted phenyl.
75 . The compound of claim 74 , wherein M is substituted with a hydrogen bond donor.
76 . The compound of claim 75 , wherein M is 2-hydroxy-phenyl.
77 . The compound of claim 71 , wherein X 5 , X 6 , X 7 and X 8 are each oxygen.
78 . The compound of claim 71 , wherein Y 5 and Y 6 are nitrogen.
79 . The compound of claim 71 , wherein Y 7 is oxygen.
80 . The compound of claim 71 , wherein R 18 and R 17 are linked to form a substituted or unsubstituted six membered ring.
81 . The compound of claim 80 , wherein said ring is aromatic.
82 . The compound of claim 71 , wherein R 14 , R 16 , R 19 , and R 20 are each hydrogen.
83 . The compound of claim 71 , wherein said compound is of formula (IIId)
wherein:
X 5 and X 6 are each independently oxygen or sulfur;
R 14 , R 16 , R 20 and each occurrence of R 21 and R 22 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, nitro, acyl, absent; or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.
84 . The compound of claim 64 , wherein said compound has no more than five hydrogen bond donors, no more than ten hydrogen bond acceptors, a molecular weight under 500, and a partition coefficient of log P under 5.
85 . A compound of formula (IVa):
wherein:
B is a substituted or unsubstituted fused cyclic or heterocyclic group;
E is substituted or unsubstituted phenyl, heterocyclic or fused cyclic group;
R 23 and R 24 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, propargyl, nitro, or acyl, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof provided said compound is not 4-[(fluoren-9-ylidenehydrazinylidene)methyl]benzoic acid; 2-[(fluoren-9-ylidenehydrazinylidene)methyl]benzoic acid; 9-oxo-fluorene-1-carboxylic acid azine with benzaldehyde; 9H-fluoren-9-ylidenehydrazone with 4-methyl benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-hydroxy benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-(1-methylethyl)-benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-methoxy benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-methoxy benzaldehyde; 9H-fluoren-9-ylidenehydrazone benzaldehyde; [4-(fluoren-9-ylidenehydrazonomethyl)phenoxy]acetic acid; 4-hydroxy-9(10H)-anthracenylidene hydrazone benzaldehyde; 9H-fluoren-9-ylidenehydrazide with 4-methyl benzoic acid; 9H-fluoren-9-ylidenehydrazone 2 methyl-benzaldehyde; 2-(fluoren-9-ylidenehydrazonomethyl)phenol; 9H-fluoren-9-ylidenehydrazone 3-hydroxy benzaldehyde; (1-phenylethylidene)hydrazone 9H-fluoren-9-one; 9H-fluoren-9-ylidenehydrazone 4-nitro-benzaldehyde; 1-naphtaldehyde azine with fluoren-9-one; 9H-fluoren-9-ylidenehydrazone 2,4-dihydroxy benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-methyl benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-fluoro benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-chloro benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-iodo benzaldehyde; (10-oxo-9(10H)-anthracenylidene)hydrazone benzaldehyde; 9H-fluoren-9-ylidenehydrazone 2,5-dihydroxy benzaldehyde; 4-(9H-fluoren-9-ylidenehydrazino)benzoic acid; fluoren-9-ylidenehydrazide benzoic acid; (diphenylmethylene)hydrazone 9H-fluoren-9-one; 9H-fluoren-9-ylidenehydrazone 4-dimethylamino benzaldehyde; 9H-fluoren-9-ylidenehydrazone 4-methoxy naphthalenealdehyde; 9H-fluoren-9-ylidenehydrazide 4-hydroxy benzoic acid; [1-(4-ethoxyphenyl)ethylidene]hydrazone 9H-fluoren-9-one; [1-(4-methylphenyl)ethylidene]hydrazone 9H-fluoren-9-one; or 9H-fluoren-9-ylidenehydrazone 2-methoxy benzaldehyde.
86 . The compound of claim 85 , wherein B comprises one or more aromatic rings.
87 . The compound of claim 85 , wherein E is substituted phenyl.
88 . The compound of claim 87 , wherein E is substituted with a hydrogen bond donor.
89 . The compound of claim 88 , wherein E is substituted with a carboxylic acid group.
90 . The compound of claim 85 , wherein R 21 is hydrogen.
91 . The compound of claim 85 , wherein said compound is of formula (IVb)
wherein:
B is a substituted or unsubstituted fused cyclic or heterocyclic group;
R 23 and R 25 are each independently selected for each occurrence from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, propargyl, nitro, or acyl, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.
92 . The compound of claim 85 , wherein said compound has no more than five hydrogen bond donors, no more than ten hydrogen bond acceptors, a molecular weight under 500, and a partition coefficient of log P under 5.
93 . A method for treating a bone disorder, comprising administering to a subject an effective amount of a compound of formula (IIa), such that said bone disorder is treated, wherein said compound of formula (IIa) is:
Q 1 -L 1 -Q 2 (IIa)
wherein:
L′ is a linking moiety;
Q 1 is an optionally substituted heterocyclic moiety comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups;
Q 2 is an optionally substituted aryl, heteroaryl, polycyclic, alkyl, alkenyl, or a heterocyclic, moiety, optionally comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
94 . A method for treating a bone disorder, comprising administering to a subject an effective amount of a compound of formula (IIIa), such that said bone disorder is treated, wherein said compound of formula (IIIa):
wherein:
X 5 and X 6 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 is oxygen, sulfur, nitrogen, or carbon;
R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, acyl, absent, or K-W;
W is an independently selected optionally substituted aryl, heteroaryl, cyclic or polycyclic group;
K is an independently selecting alkyl, alkenyl, alkynyl, oxo, or amino group; or a pharmaceutically acceptable salt, tautomer, ester or prodrug thereof;
provided that when Y 5 is nitrogen, R 13′ is absent; when Y 6 is oxygen or sulfur, R 14 and R 14′ are each absent; when Y 6 is carbon, R 14′ is absent; and two of R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ , not covalently bonded to the same atom, are W.
95 . A method for treating a bone disorder, comprising administering to a subject an effective amount of a compound of formula (IVa), such that said bone disorder is treated, wherein said compound of formula (IVa):
wherein:
B is a substituted or unsubstituted fused cyclic or heterocyclic group;
E is substituted or unsubstituted phenyl, heterocyclic or fused cyclic group;
R 23 and R 24 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, propargyl, nitro, or acyl, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.
96 . A method for treating a bone disorder, comprising administering to a subject an effective amount of a compound of claim 53 , such that said bone disorder is treated.
97 . A method for increasing osteoblast activity, comprising contacting an osteoblast with an effective amount of a compound of formula (IIa), such that osteoblast activity is increased, wherein said compound of formula (IIa) is:
Q 1 -L 1 -Q 2 (IIa)
wherein:
L′ is a linking moiety;
Q 1 is an optionally substituted heterocyclic moiety comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups;
Q 2 is an optionally substituted aryl, heteroaryl, polycyclic, alkyl, alkenyl, or a heterocyclic moiety, optionally comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
98 . A method for increasing osteoblast activity, comprising contacting an osteoblast with an effective amount of a compound of formula (IIIa), such that osteoblast activity is increased, wherein said compound of formula (IIIa) is:
wherein:
X 5 and X 6 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 is oxygen, sulfur, nitrogen, or carbon;
R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, acyl, absent, or K-W;
W is an independently selected optionally substituted aryl, heteroaryl, cyclic or polycyclic group;
K is an independently selecting alkyl, alkenyl, alkynyl, oxo, or amino group;
or a pharmaceutically acceptable salt, tautomer, ester or prodrug thereof;
provided that when Y 5 is nitrogen, R 13′ is absent; when Y 6 is oxygen or sulfur, R 14 and R 14′ are each absent; when Y 6 is carbon, R 14′ is absent; and two of R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ , not covalently bonded to the same atom, are W.
99 . A method for increasing osteoblast activity, comprising contacting an osteoblast with an effective amount of a compound of formula (IVa), such that osteoblast activity is increased, wherein said compound of formula (IVa) is:
wherein:
B is a substituted or unsubstituted fused cyclic or heterocyclic group;
E is substituted or unsubstituted phenyl, heterocyclic or fused cyclic group;
R 23 and R 24 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, propargyl, nitro, or acyl, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.
100 . A method for increasing osteoblast activity, comprising contacting an osteoblast with a compound of claim 53 , such that osteoblast activity is increased.
101 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (IIa):
Q 1 -L 1 -Q 2 (IIa)
wherein:
L′ is a linking moiety;
Q 1 is an optionally substituted heterocyclic moiety comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups;
Q 2 is an optionally substituted aryl, heteroaryl, polycyclic, alkyl, alkenyl, or a heterocyclic moiety, optionally comprising two or more nitrogen ring atoms and one, two or three carbonyl or thiocarbonyl groups, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.
102 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (IIIa):
wherein:
X 5 and X 6 are each independently oxygen or sulfur;
Y 5 is nitrogen or carbon;
Y 6 is oxygen, sulfur, nitrogen, or carbon;
R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, acyl, absent, or K-W;
W is an independently selected optionally substituted aryl, heteroaryl, cyclic or polycyclic group;
K is an independently selecting alkyl, alkenyl, alkynyl, oxo, or amino group;
or a pharmaceutically acceptable salt, tautomer, ester or prodrug thereof;
provided that when Y 5 is nitrogen, R 13′ is absent; when Y 6 is oxygen or sulfur, R 14 and R 14′ are each absent; when Y 6 is carbon, R 14′ is absent; and two of R 13 , R 13′ , R 14 , R 14′ , R 15 , and R 15′ , not covalently bonded to the same atom, are W.
103 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (IVa):
wherein:
B is a substituted or unsubstituted fused cyclic or heterocyclic group;
E is substituted or unsubstituted phenyl, heterocyclic or fused cyclic group;
R 23 and R 24 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, cyano, thiol, amino, propargyl, nitro, or acyl, or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof.
104 . A pharmaceutical composition comprising a compound of claim 53 and a pharmaceutically acceptable carrier.
105 . The pharmaceutical composition of claim 103 , wherein said composition comprises an effective amount of said compound.
106 . The pharmaceutical composition of claim 105 , wherein said effective amount is effective to treat a bone disorder.