Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Abstract

Objective. To characterize the clinical and histopathologic changes in a rat model of broad-spectrum matrix metalloproteinase (MMP)-induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.Methods. Male Lewis rats weighing 150-180 gm were administered 10-30 mg of the broad-spectrum MMP inhibitor marimastat over a 2-week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.Results. Marimastat-treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high-stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat-treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.Conclusion. This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

“…The exposure on day 14 in the combined group of animals treated with ALS 1-0635 at100 mg/kg/day was 743 g/hour/ml (0-24-hour area under the curve). Such analyses were not performed in samples from Marimastat-treated animals since the toxicity findings were consistent with those reported in the literature (8).…”

“…However, clinical utility of these broad-spectrum MMP inhibitors has been limited by debilitating, dose-and duration-dependent MSS (fibroplasia or tendinitis) in humans (6,7). Although no specific MMP has been implicated, it is believed that nonselective inhibition of multiple MMPs is the primary reason for the observed toxicity (8). Therefore, our strategy for development of DMOADs was to focus on identification of highly selective allosteric MMP-13 inhibitors free of hydroxamic acid or other zinc-chelating functional groups that contribute to inhibition of multiple MMPs.…”

“…The rat model of MSS was used to assess whether MMP-13 inhibitors have the joint toxicity associated with the broad-spectrum MMP inhibitors (8). These experiments were conducted at Seventh Wave Laboratories (Chesterfield, MO).…”

“…MSS is generally reversible upon cessation of drug treatment (6,7). No specific MMP has been implicated, and it is believed that nonselective inhibition of multiple MMPs is the primary cause of this toxicity (8). Therefore, current drug development strategies for treatment of OA are focused on inhibition of specific MMPs implicated in the disease process.…”

Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)

“…7 Even though such MMP inhibitors like Marimastat, Batimastat, CGS-27023A, and Prinomastat demonstrated significant preclinical efficacy in vivo, they exhibited musculoskeletal side-effects in humans. 8 The identification of selective and potent inhibitors, preferably without obvious metal chelating groups, was our goal. Unfortunately there are limited examples of ADAMTS-4 inhibitors with potent activity and high selectivity reported in the literature.…”