Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Abstract

SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2 and -9, has shown efficacy in several animal models of neurological diseases. One of the greatest challenges in the development of therapeutics for neurological diseases is the inability of drugs to cross the blood-brain barrier. A sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection was developed to measure levels of SB-3CT, its active metabolite, the α-methyl analogue, and its p-hydroxy metabolite in plasma and brain. The compounds are rapidly absorbed and are readily distributed to the brain. The pharmacokinetic properties of these gelatinase inhibitors and the efficacy shown by SB-3CT in animal models of stroke, subarachnoid hemorrhage, and spinal cord injury indicate that this class of compounds holds considerable promise in the treatment of diseases of the central nervous system. KEYWORDS: Gelatinase inhibitors, matrix metalloproteinases, brain delivery, SB-3CT S B-3CT (compound 1, Figure 1), is a thiirane-based inhibitor that is selective for matrix metalloproteinase (MMP)-2 and -9, 1 also known as gelatinases. This compound has shown efficacy in a number of neurological diseases, including blocking laminin degradation by MMP-9 and rescuing neurons from apoptosis after transient focal cerebral ischemia, 2 preventing laminin degradation after subarachnoid hemorrhage, 3 reducing cerebral vasopasm caused by subarachnoid hemorrhage, 4 reducing the infiltration of monocytes into the injured spinal cord, 5 and decreasing extravasation and apoptotic cell death after spinal cord injury. 6 The compounds of the thiirane class have a unique mechanism of action, involving ring-opening of the thiirane ring at the active site of gelatinases and generation of the thiolate, which is a picomolar and tight-binding inhibitor. 7The blood-brain barrier (BBB) forms a physical separation between circulating blood and the brain parenchyma and consists of tight junctions around endothelial cells surrounded by basement membrane. The BBB prevents pathogens and large hydrophilic molecules from entering the brain, while allowing transport of substances needed by the central nervous system (CNS) such as glucose, fatty acids, and vitamins. One of the most challenging issues in the development of therapeutics for neurological diseases is the inability of drugs to cross the BBB. In fact, greater than 98% of small-molecule drugs and 100% of large-molecule therapeutics do not cross the BBB. Only 5% of small-molecule drugs in the Comprehensive Medicinal Chemistry database treat a mere four CNS diseases: depression, schizophrenia, chronic pain, and epilepsy.9,10 The vast majority of CNS disorders, including debilitating diseases

The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination

“…SB-3CT and ND-322 have also been shown to cross the blood/brain barrier[27, 28], indicating that ND-322 could potentially be used for the treatment of melanoma brain metastasis, which affects up to 40% of metastatic melanoma patients[29]. Finally, in our study ND-322 was well tolerated by mice, similarly to what was previously shown in a model of wound healing[30] This aspect is important as earlier trials with broad-spectrum MMP inhibitors failed mostly due to severe side effects such as musculoskeletal pain and inflammation, accompanied by negligible anti-cancer effects [10, 11].…”

Very long-term memories may be stored in the pattern of holes in the perineuronal net

“…Remarkably, after a single i.p. injection, SB-3CT rapidly crosses the blood-brain barrier and then washes out in just a few minutes (51). This convenient route of administration and rapid pharmacokinetics should permit more precise delineation of the interval, during which time MMP-2/-9 activity is required during acquisition of fear memories.…”

Development of a Method and Validation for the Quantitation of FruArg in Mice Plasma and Brain Tissue Using UPLC–MS/MS

“…Gooyit et al detected SB-3CT, a selective inhibitor of matrix metalloproteinase-2 and -9, present in similar concentrations in the brain tissue (5.0 ± 0.8 pmol/mg at 10 min), after the administration of comparable dosages to this study (25 mg/kg). 39 The dose detected in the brain may not represent the effective dose for FruArg, and further analysis of the dose range is planned.…”