Composition, uses, and methods of treating spinal disc degeneration through sonic hedgehog signaling pathway

A method for repairing or improving the function of an injured intervertebral disc or a intervertebral disc damaged from inflammation in a human subject, the method comprising administering an amount of a sonic hedgehog signaling pathway activator effective for repairing or improving the function of an intervertebral disc in the subject, wherein the SHH signaling pathway activator is selected from the following:

• (i) SAG,
• (ii) SHH
• (iii) GSA-10
• (iv) purmorpamine
• (v) a compound of the following Formula I:
• where Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings;
• Y, independently for each occurrence, is absent or represent s-N(R)—, —O—, —S—, or —Se—;
• X is selected from —C(═O)—, —C(═S)—, —S(O2)-, —S(O)—, —P(═O)(OR)—, and a methylene group optionally substituted with 1-2 groups selected from lower alkyl, alkenyl, and alkynyl groups;
• M represents, independently for each occurrence, a substituted or un-substituted methylene group selected from —CH2-, —CHF—, —CHOH—, —CH(Me)-, and —C(═O)—, or two M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in Mj form all or part of a cyclic structure;
• R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, alkynyl, alkenyl, or alkyl, or two R taken together may form a 4- to 8-membered ring optionally with N;
• Cy′ represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl;
• j represents, independently for each occurrence, an integer from 0 to 10;
• and i represents, independently for each occurrence, an integer from 0 to 5;
• (vi) a compound of the following Formula II:
• where X═C, N, or N≡C—(CH2)a—C, where 0</=a</=5;
• Y═R or —O—(CH2)b—CH3, where 0</=b</=5;
• Z═H, CH3 or CH(CH2)c, where 0</=c</=5, and
• (vii) a compound of the following Formula III:
• R6 is selected from H and halo;
• R9 is selected from H and halo;
• R11 is selected from H, hydroxy, oxo and halo;
• R16 is selected from alkyl, —OR′, —SR′, —N(R′)2, —NH—C(O)R″ and —NR—S(O)n-R″, or may be taken together with R17 to form a ring;
• R17 is selected from hydroxy and —OC(Z)R″, or may be taken together with R16 to form a ring;
• Y is selected from a bond, O and S;
• X is selected from a bond and CH2;
• W is selected from alkyl, hydroxy, halo and —OC(O)R″;
• each R′ is independently H, alkyl, aryl, heterocyclyl or heteroaryl;
• each R″ is independently alkyl;
• Z is O or S;
• and
• n is 1 or 2;
• wherein when R16 and R17 are taken together to form a ring, they together form the group —O—C(Ra)2-O—, wherein each Ra is independently alkyl or two Ra are taken together to form a ring.

A method for alleviating one or more symptoms of an intervertebral disc degeneration in a human subject, the method comprising administering an amount of a sonic hedgehog signaling pathway activator effective for alleviating one or more symptoms of an intervertebral disc degeneration in the subject, wherein the SHH signaling pathway activator selected from the following:

• (viii) SAG,
• (ix) SHH
• (x) GSA-10
• (xi) purmorpamine
• (xii) a compound of the following Formula I:
• where Ar and Ar′ independently represent substituted or unsubstituted aryl or heteroaryl rings;
• Y, independently for each occurrence, is absent or represent s-N(R)—, —O—, —S—, or —Se—;
• X is selected from —C(═O)—, —C(═S)—, —S(O2)-, —S(O)—, —P(═O)(OR)—, and a methylene group optionally substituted with 1-2 groups selected from lower alkyl, alkenyl, and alkynyl groups;
• M represents, independently for each occurrence, a substituted or un-substituted methylene group selected from —CH2-, —CHF—, —CHOH—, —CH(Me)-, and —C(═O)—, or two M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in Mj form all or part of a cyclic structure;
• R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, alkynyl, alkenyl, or alkyl, or two R taken together may form a 4- to 8-membered ring optionally with N;
• Cy′ represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl;
• j represents, independently for each occurrence, an integer from 0 to 10;
• and i represents, independently for each occurrence, an integer from 0 to 5;
• (xiii) a compound of the following Formula II:
• where X═C, N, or N≡C—(CH2)a—C, where 0</=a</=5;
• Y═R or —O—(CH2)b—CH3, where 0</=b</=5;
• Z═H, CH3 or CH(CH2)c, where 0</=c</=5, and
• (xiv) a compound of the following Formula III:
• R6 is selected from H and halo;
• R9 is selected from H and halo;
• R11 is selected from H, hydroxy, oxo and halo;
• R16 is selected from alkyl, —OR′, —SR′, —N(R′)2, —NH—C(O)R″ and —NR—S(O)n-R″, or may be taken together with R17 to form a ring;
• R17 is selected from hydroxy and —OC(Z)R″, or may be taken together with R16 to form a ring;
• Y is selected from a bond, O and S;
• X is selected from a bond and CH2;
• W is selected from alkyl, hydroxy, halo and —OC(O)R″;
• each R′ is independently H, alkyl, aryl, heterocyclyl or heteroaryl;
• each R″ is independently alkyl;
• Z is O or S;
• and
• n is 1 or 2;
• wherein when R16 and R17 are taken together to form a ring, they together form the group —O—C(Ra)2-O—, wherein each Ra is independently alkyl or two Ra are taken together to form a ring.