John F. DiJoseph

The discovery of anthranilic acid-Based MMP inhibitors. Part 2: SAR of the 5-position and P11 groups

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.

Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach

Alpha-2 receptor activation mediates the inhibition of a number of gastrointestinal functions including gastric and intestinal secretions. Alpha-2 receptors are located in the brain and presynaptically on cholinergic nerve terminals; activation of either inhibits vagus nerve activity. Intestinal secretions are inhibited by postsynaptic alpha-2 receptors located on intestinal epithelial cells. Agents which selectively activate alpha-2 receptors in the gut may therefore be beneficial in treating gastric ulcers and diarrheal states. Two such agents which activate alpha-2 receptors in the gut are WHR-1370A [1-n-butoxy-3-(2,6-dimethylphenylcarbamoyl) guanidine hydrochloride] and lidamidine. WHR-1370A is a potent gastric antisecretory and antiulcer agent which inhibits the release of acetylcholine from the vagus nerve. WHR-1370As activity is blocked by yohimbine. Lidamidine is a clinically effective antidiarrheal agent. Lidamidines response is partially inhibited by yohimbine in animal diarrheal models. Alpha-2 agonists represent a new class of drugs which have a promising future in the treatment of gastrointestinal disorders.

The discovery of anthranilic acid-based MMP inhibitors. Part 1: SAR of the 3-position

A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, and MMP-13 was prepared and evaluated both in vitro and in vivo. The most potent compound, 6e, has in vivo activity in a rat sponge-wrapped cartilage model.

Therapeutic blood levels of sirolimus (rapamycin) in the allografted rat.

A study was conducted to determine the relationship among oral dose, trough whole blood levels, graft survival, and side effects in sirolimus-treated allografted rats. The heterotopic heart allograft model using Brown Norway donors and Lewis rat recipients was used. Rats were dosed daily with sirolimus or vehicle until graft failure or up to a maximum of 28 days. Upon graft failure, rats were bled for measurement of trough blood levels of drug and tissues sent for histopathologic analysis. Sirolimus blood concentration correlated positively with dose and graft survival. Significant graft survival occurred at whole blood trough levels of 0.5 ng/ml achieved at the 0.3 mg/kg/day dose. Analysis of the concentration-effect data using a sigmoidal Emax model calculated a whole blood EC50 of 2.0 ng/ml for graft survival. With mean trough concentrations of 7 ng/ml and higher, grafts survived after cessation of drug treatment. At the 0.8 mg/kg/day dose, there was a significant decrease in body weight gain in the rats. Histopathologic examination of sirolimus-treated animals detected thymic and lymphoid atrophy, both considered pharmacologic extensions of sirolimuss immunosuppressive activity and focal myocardial degeneration, an exacerbation of a spontaneous occurring lesion. These results demonstrate that sirolimus prolongs graft survival in rat in a concentration dependent manner with therapeutic whole blood levels of about 10 ng/ml.

Renal effects of rapamycin in the spontaneously hypertensive rat

The effects of rapamycin (RAPA), administered at therapeutic doses, were investigated in the spontaneously hypertensive rat (SHR). Additionally, the reversibility of RAPAs renal effects was investigated at a supratherapeutic dose. At doses that were active in preventing heart and kidney allograft rejection in the rat (0.01–0.08 mg/kg i.v.), RAPA had no effect on kidney function or rat body weight gain. At higher doses (0.8 mg/kg), RAPA produced significant changes in kidney function parameters and caused a loss in body weight. Histopathologic changes, including necrotizing vasculopathy and tubular atrophy, were noted at therapeutic doses. The effects of RAPA on kidney function were completely reversible after a 2-week washout period, though the histopathologic changes were still evident. These studies demonstrate that RAPA does not impair kidney function at therapeutic doses when administered for 2 weeks but does appear to accelerate the naturally occurring renal lesions of the SHR.

The discovery of anthranilic acid-based mmp inhibitors. Part 3: incorporation of basic amines

Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.

The synthesis and biological activity of a novel series of diazepine MMP inhibitors.

A novel series of diazepine-based hydroxamic acid inhibitors of MMP-1, MMP-9, and MMP-13 were prepared and evaluated both in vitro and in vivo.

Benzodiazepine inhibitors of the MMPs and TACE.

A series of benzodiazepine inhibitors of the MMPs and TACE has been developed. These compounds display an interesting selectivity profile and should be useful tools for exploring the biological relevance of such selectivity.

Heteroaryl and Cycloalkyl Sulfonamide Hydroxamic Acid Inhibitors of Matrix Metalloproteinases

Heteroaryl and cycloalkyl sulfonamide-hydroxamic acid MMP inhibitors were investigated. Of these, the pyridyl analogue 2 is the most potent and selective inhibitor of MMP-9 and MMP-13 in vitro.

The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases

A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).