Isoprenoid pathway inhibitors for stimulating bone growth
AssigneesZymoGenetics, Inc., OsteoScreen IP, LLC
InventorsShirley R. Gasper, Robert R. West, Theresa Martinez, Kirk G. Robbins, Patricia A. McKernan, Nand Baindur, Virender M. Labroo, Gregory R. Mundy
Life of this patent
Estimating the term…
Abstract
Compounds of the formula 1 wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C; Y is of the formula 2 or a stereoisomer thereof, wherein R1 is substituted or unsubstituted alkyl; each R2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C); R3 is H, hydroxy, or alkoxy (1-6C); or Y is of the formula 3 wherein each n is 1, Z is N,
Claims35
A method to enhance bone formation in a vertebrate animal which method comprises administering to a vertebrate subject in need of such treatment an amount of a composition comprising a statin compound of the formula:
- 13
- wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C;
- Y is of the formula
- 14
- or a stereoisomer thereof,
- wherein R1 is substituted or unsubstituted alkyl;
- each R2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C);
- R3 is H, hydroxy, or alkoxy (1-6C);
- or
- Y is of the formula
- 15
- wherein each n is 1,
- Z is N,
- K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR6— wherein R6 is H or linear, branded or cyclic alkyl (1-6C),
- R5 is H or linear, branched or cyclic alkyl, and
- R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C, wherein bone formation is effected.
A pharmaceutical composition in unit dosage form to enhance bone formation in a vertebrate animal which composition comprises a pharmaceutically acceptable excipient and an amount, effective to promote bone formation, of a compound of the formula:
- 16
- wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C;
- Y is of the formula
- 17
- or a stereoisomer thereof,
- wherein R1 is substituted or unsubstituted alkyl;
- each R2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C);
- R3 is H, hydroxy, or alkoxy (1-6C);
- or
- Y is of the formula
- 18
- wherein each n is 1,
- Z is N,
- K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR6— wherein R6 is H or linear, branded or cyclic alkyl (1-6C),
- R5 is H or linear, branched or cyclic alkyl, and
- R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C.
A method to identify a compound that is useful in treating bone disorders in vertebrates which method comprises
- contacting said compound with an assay mixture for the activity of an enzyme in the isoprenoid pathway;
- determining the activity of the enzyme in the presence as compared to the absence of said compound;
- wherein a decrease of activity of said enzyme in the presence as opposed to the absence of said compound indicates that the compound will be useful in treating bone disorders in vertebrates.
A method to identify a compound useful to treat bone disorders in vertebrates which method comprises
- contacting a candidate compound with an expression system wherein said expression system comprises a control sequence associated with an enzyme in the isoprenoid synthesis pathway operably linked to a reporter gene;
- comparing the expression of the reporter gene in the presence and absence of the compound;
- wherein a decrease in the expression of the reporter gene in the presence as compared to the absence of the compound indicates the compound will be useful in treating bone disorders in vertebrates.
Dependencies are inferred from the claim text.