Hydroxamic acid thrombospondin peptide analog that inhibits aggrecanase activity
OwnerMichael Tortorella, Jinhai Wang +1inventors
InventorsMichael Tortorella, Jinhai Wang, Rodney L. Balhorn
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Abstract
The present invention concerns the generation of hydroxamic acid thrombospondin-peptide analogs that inhibit aggrecanase activity. These analogs are useful in the treatment of diseases characterized by cartilage degradation, such as osteoarthritis, rheumatoid arthritis spondylarthropathies, and septic arthritis. The invention describes a novel small molecule, enzyme inhibitor that binds both the enzyme and its naturally occurring substrate.
Claims15
The therapeutic use of hydroxamic acid thrombospondin peptide analog compounds for the treatment of diseases characterized by in vivo cartilage degradation, selected from osteoarthritis, rheumatoid arthritis, spondylarthropathies, and septic arthritis.
The use of hydroxamic acid thrombospondin peptide analog compounds for the inhibition of ADAMTS-4/ADAMTS-5 in vitro or in vivo.
The hydroxamic acids having the structures suitable for use in preparing thrombospondin peptide analog compounds found in FIGS. 1A to 1J as shown:
- 3
- wherein for the hydroxamic acid structure HO—NH—(C═O)—CH2—CH(—CH2—CH(CH3)2)—(C═O)—V—, the V (valine) can be another amino acid to connect to the amino acid sequence of about 10 or more amino acids.
The compounds selected from the group:
- 5 HO—NH—(CO═O)—CH2—CH(—CH2—CH(CH3)2)—(C═O)—V— —QAGGWGPWGPWGDSSAT;
- (˜11′A) HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V— SNISQAGGWGPWGPWGDSSAT;
- (˜22′A);
- HO—NH—(C═O)—CH2—CH(CH(CH3)2—(C═O)—V— —LQDSNISQAGGWGPWGPWGDSSAT;
- and (˜33′A) HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V— MDQLQDSNISQAGGWGPWGPWGDSSAT (˜44′A)
A method of treatment to arrest cartilage degradation in vivo in a mammal preferably a human, which method comprises administering a therapeutically effective
A pharmaceutical compositions for use in the treatment of diseases characterized by in vivo cartilage degration, which composition comprises structures selected from the groups consisting of
- 4
- characterized by in vivo cartilage degration, which composition compresses structures selected from the group consisting of
- 8 HO—NH—(C═O)—CH2—CH(—CH2—CH(CH3)2)—(C0)—V--QAGGWGPWGPWGDSSAT (˜11′A);
- HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V--SNISQAGGWGPWGPWGDSSAT (˜22′A);
- HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V--LQDSNISQAGGWGPWGPWGDSSAT (˜33′A);
- and HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V--MDQLQDSNISQAGGWGPWGPWGDSSAT (˜44′A)
- and a pharmaceutically acceptable excipient.
The pharmaceutical composition of claim 12 as
- 9 HO—NH—(C═O)—CH2—CH(—CH2—CH(CH3)2)—(C═O)—V- (˜11′A) -QAGGWGPWGPWGDSSAT
The pharmaceutical composition of claim 12 as
- 10 HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V--SNIS (˜22′A) QAGGWGPWGPWGDSSAT
The pharmaceutical composition of claim 12 as
- 11 HO—NH—(C═O)—CH2—CH(CH(CH3)2)—(C═O)—V--LQDS (˜33′A) NISQAGGWGPWGPWGDSSAT
Dependencies are inferred from the claim text.