Thiirane Class of Gelatinase Inhibitors as a Privileged Template that Crosses the Blood–Brain Barrier
The gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) play important roles in the pathophysiology of several diseases, including cancer metastases, neurological diseases, and chronic wounds. MMPs also mediate beneficial repair and recovery functions. Thus, the use of selective MMP inhibitors is required to avoid side effects. The prototype gelatinase inhibitor SB-3CT displays potency and selectivity towards the gelatinases. SB-3CT contains a thiirane ring that involves a reaction catalyzed by the gelatinases, which results in slow-binding and/or tight-binding inhibition. This unique mechanism of action is at the root of selectivity enjoyed by the thiirane class of inhibitors. We have synthesized and evaluated >500 thiirane derivatives. SB-3CT has shown efficacy in numerous animal models of disease, including cancer metastasis, stroke, traumatic brain injury, and diabetic wound healing. The members of the thiirane class cross the blood–brain barrier (BBB), achieve therapeutic concentrations in the brain, and do not accumulate in the brain. These desirable attributes of the thiiranes indicate that this class of gelatinase inhibitors holds great promise for intervention of neurological diseases and chronic wounds.