DMP 777

DMP 777(L-694458) is a potent, selective, and orally active human leukocyte elastase (HLE) inhibitor.

Degradation kinetics of DMP 777, an elastase inhibitor.[Pubmed:8987077]

Pharm Res. 1996 Dec;13(12):1815-20.

PURPOSE: The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development. METHODS: The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples. RESULTS: The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves beta-lactam ring opening. The beta-lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the KOH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the beta-lactam nitrogen making it a good leaving group. CONCLUSIONS: The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.

Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777.[Pubmed:16614949]

Dig Dis Sci. 2006 Mar;51(3):431-9.

Atrophic gastritis, characterized as parietal cell loss or oxyntic atrophy, is the primary event in the evolution of the spectrum of metaplastic and hyperplastic lineage changes thought to predispose to gastric neoplasia. A number of animal models have provided insights into the lineage changes induced by oxyntic atrophy. Recently, we have reported a model for pharmacological induction of oxyntic atrophy with DMP-777. DMP-777 ablates parietal cells selectively and leads to the gastric cell lineage changes including foveolar hyperplasia and spasmolytic polypeptide expressing metaplasia (SPEM). Previous investigations showed that DMP-777 dissipated a gastric tubulovesicle proton gradient without impairing the H/K-ATPase activity, consistent with its pharmacological action as a parietal cell-specific protonophore which could induce parietal cell necrosis through backwash of luminal acid into actively secreting cells. We hypothesized that, if DMP-777 was acting as a parietal cell protonophore, then suppression of acid secretion should protect parietal cells from the toxic effects of the drug. In this study, we pretreated and coadministered the proton pump inhibitor omeprazole with DMP-777 to determine the effect of active acid secretion inhibition on the DMP-777-induced histologic changes in the stomachs of male rats. Omeprazole pretreatment ameliorated DMP-777-induced parietal cell loss as well as foveolar hyperplasia. These results indicate that active acid secretion is required for DMP-777 cytotoxicity, consistent with its suggested behavior as a parietal cell-specific protonophore.

Isolation and identification of a degradation product in a capsule formulation containing the elastase inhibitor, DMP 777.[Pubmed:11272322]

J Pharm Biomed Anal. 2001 Feb;24(4):651-7.

An unexpected degradation product, greater than 0.10%, was observed in a DMP 777 capsule formulation stored at 40 degrees C/75% r.h. for 3 months and 25 degrees C/60% r.h. for 2 years. The degradant of interest was prepared in quantity by refluxing the drug substance in dilute acid. A preparative HPLC method was developed to separate the various degradants and to collect each as a separate fraction. Each fraction was analyzed by the analytical HPLC gradient test method to assure positive identification of each peak and to correlate each peak to the original capsule sample. Key isolated degradation products were used for structure elucidation with mass spectrometry and NMR. The major degradant of interest in the capsule formulation was found to be a carboxylic acid resulting from the acid hydrolysis of an amide bond.