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lesions (Figure 4).38 The in ViVo efficacy study in rabbits
provided greater confidence in rationale (CIR) for this approach
of using MMP-13-specific inhibitors to treat OA.
Conclusion
In summary, the HTS hit thiazolopyrimidinedione 7 is a
MMP-13-specific inhibitor, which imparts its specificity by
binding the unique S1′-specificity pocket. Our extensive SAR
investigation resulted in amide pyrido[3,4-d]pyrimidin-4-ones
10 as MMP-13-selective inhibitors (specific versus other MMPs)
that bind to the unique S1′-specificity pocket and do not bind
to the Zn2+ ion. Some derivatives, such as 10a, possess
favorable ADME and safety profiles. More significantly, our
positive cartilage protection in ViVo study in rabbits using 10a
provided increased CIR for this approach of using MMP-13-
specific inhibitors to treat OA.
Supporting Information Available: 1H NMR spectra and data
and MS(APCI) data of all products and melting points and CHN
elemental analysis data for all solid samples. This material is
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