Isoprenoid pathway inhibitors for stimulating cartilage growth

Abstract

Compounds of the formula 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 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 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, promote bone formation and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation. Also disclosed is a method to identify additional compounds which are inhibitors of enzymes in the isoprenoid scheme especially of HMG-CoA reductase which results in prenylation of proteins and in the synthesis of steroids or of inhibitors of their production which are useful in treating bone disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 10 / 652,159, filed Aug. 29, 2003, which is a continuation of U.S. Ser. No. 09 / 848,839, filed 3 May 2001, now U.S. Pat. No. 6,642,216, which is a divisional of U.S. Ser. No. 09 / 488,380, filed 20 Jan. 2000, now U.S. Pat. No. 6,376,476, which is a continuation-in-part of U.S. Ser. No. 09 / 096,631 filed 12 Jun. 1998, now abandoned, and of U.S. Ser. No. 09 / 096,957, filed 12 Jun. 1998, now U.S. Pat. No. 6,080,779, which are continuations-in-part of U.S. Ser. No. 08 / 989,862, filed 12 Dec. 1997, now U.S. Pat. No. 6,022,887, which claims benefit of U.S. Ser. No. 60 / 032,893 filed 13 Dec. 1996. The entire contents of each of these documents are incorporated herein by reference.TECHNICAL FIELD [0002] The invention relates to screening methods for compositions and to methods to use these compositions in treating bone disorders in vertebrates including fractures and cartilage disorders. More specifica...

AI Technical Summary

Benefits of technology

[0020] In still another aspect, the invention is directed to methods to identify additional compounds which are useful in methods to treat bone disorders by assessing their ability to inhibit enzymes significant in the isoprenoid synthesis pathway, especially HMG-CoA reductase, but also including subsequent steps resulting in the synthesis of steroid...

Problems solved by technology

Although the BMPs are potent stimulators of bone formation in vitro and in vivo, there are disadvantages to their use as therapeutic agents to enhance bone healing.

This suggests that BMPs may have effects on many tissues in addition to bone, potentially limiting their usefulness as therapeutic agents when administered systemically.

These disadvantages impose severe limitations to the development of BMPs as therapeutic agents.

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