Highly selective inhibitors of ADAMS activity
The present invention relates to compounds of general formula (i) where a proper combination of the substituents from A to ZBG gives structural characteristics able to strongly discriminate the selectivity between sheddases like TACE (ADAM17) and other anti-target proteases (MMPs, other ADAMs and ADAMTSs) whose inhibition is responsible for severe side effects. The aim of the invention is to obtain therapeutic solutions (i) with an higher safety profile with respect to known compounds. The advantage of this invention is having compounds (i, es. 21) with an high potency and selectivity of action, low toxicity and good bioavailability.
Compounds of formula (i) are able to inhibit ADAM17 (TACE) activity in the nanomolar range by sparing several MMPs. On this basis, these molecules (i, es. 21) promise a significantly higher safety profile with respect to already known broad- spectrum inhibitors, thanks to the lack of effect on the anti-target zinc proteases. In the past, the non-specific inhibition of anti-target proteases has been the main cause of the failure of clinical trials conducted on MMPs inhibitors for use in cancer therapy [Science 2002, 295, 2387; British Journal of Cancer, 2006, 1]. A selective activity on the therapeutic target by using compounds (i, es. 21) will lead to a reduction of drug doses, elimination of pro-carcinogenic effects due to non-selective inhibition of antitarget proteases and to less side effects and toxicity in long-term treatments.
- Therapeutic or diagnostic purpose in immunology, for anti-sheddase activity modulating immune system cells (NK/T cell);
- Therapeutic or diagnostic purpose for tumors, cardiovascular diseases, rheumatoid arthritis, viral/bacterial infections, angio-/lympho- angiogenesis, neurodegeneration.
- High selectivity for ADAM17 with increased therapeutic safety and reduction of pro-carcinogenic effects;
- Good bioavailability/reduced cytotoxicity;
- Simple synthetic preparation and/or diagnostic labeling;
- Shedding modulation of TNFα, TGF-α, EGFR, ErbB, HER3, ALCAM, CD16, MICA /-B.