Design and identification of selective HER-2 sheddase inhibitors via P1′ manipulation and unconventional P2′ perturbations to induce a molecular metamorphosis

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1′ group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure–activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2′ moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2′ group effecting global conformational changes.

Figure optionsDownload as PowerPoint slide