Identification of potent and selective TACE inhibitors via the S1 pocket.
ABSTRACT By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
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ABSTRACT: Introduction: Tumor necrosis factor-α (TNF-α) is a key player in inflammation and joint damage in rheumatoid arthritis (RA). One treatment approach to exclude TNF-α from the biological system is by inhibiting tumor necrosis factor-alpha converting enzyme (TACE), the enzyme responsible for the production of its active form. To date, a number of TACE inhibitors have been reported in the literature from various strategies and methods. Areas covered: The following article presents the design and development strategies for the discovery of novel TACE inhibitors which could be of therapeutic utility for the alleviation of inflammatory conditions. The review is based on literature of the subject from 2005 onward. Expert opinion: Discovery of a selective TACE inhibitor has remained a major goal for many academic and pharmaceutical industrial research laboratories for quite some time. Identification of selective TACE inhibitors has proved elusive until recently due to structural similarities between TACE and MMPs. The differences in the shape and size of the S1' pocket of TACE and MMPs could be exploited to design selective TACE inhibitors devoid of any MMP inhibitory activity in the near future. It would be a Herculean task to develop a specific TACE inhibitor for clinical treatment of RA because binding subsites of TACE and MMPs are quite similar. However, developments taking place currently in the field as well as in the application of molecular modeling techniques at a wider scale could yet provide clinically useful selective TACE inhibitors in the not too distant future.Expert Opinion on Drug Discovery 12/2012; · 2.30 Impact Factor
- Journal of Molecular Modeling 01/2011; 17(1):9. · 1.98 Impact Factor
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ABSTRACT: A four step preparative scale synthesis of eight 2-alkyl- and arylsubstituted thiazole-4-sulfonyl chlorides from chloralamides is reported. Good yields and easy availability of starting materials are valuable advantages of the procedure that gives access to formerly unattainable building blocks.Synthetic Communications 01/2012; 42(19):2866-2875. · 1.06 Impact Factor