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Chemical Compound Review:

DMP-777 (2S)-N-[(1R)-1- benzo[1,3]dioxol-5- ylbutyl]...

Synonyms: DMP777, CHEMBL310871, AG-E-06340, SureCN6538142, ANW-64940, ...

Goldenring, J.R. et al., Vincent, S.H. et al., Ogawa, M. et al., Ogawa, M. et al., Raghavan, K.S. et al.

Goldenring, Ray, Coffey, Meunier, Haley, Barnes, Car,

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Disease relevance of DMP 777

RESULTS: Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria [1].
DMP-777 elicits a rapid loss of parietal cells followed by the emergence of foveolar hyperplasia and spasmolytic polypeptide (SP)-expressing metaplasia (SPEM) [2].
Omeprazole pretreatment ameliorated DMP-777-induced parietal cell loss as well as foveolar hyperplasia [3].

High impact information on DMP 777

Direct effects of DMP 777 on parietal cells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acridine orange fluorescence and H(+),K(+)-adenosine triphosphatase (ATPase) activity in isolated tubulovesicles [1].
Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa [1].
CONCLUSIONS: DMP 777 acts as a protonophore with specificity for parietal cell acid-secretory membranes [1].
As in wild-type mice, treatment with DMP-777 for 7 days did elicit SPEM in SP/TFF2-deficient mice [2].
In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and 2C isozymes, and in both monkey and human liver microsomes the compound acted as an inhibitor of testosterone 6beta-hydroxylation [4].

Biological context of DMP 777

Degradation kinetics of DMP 777, an elastase inhibitor [5].
DMP-777 ablates parietal cells selectively and leads to the gastric cell lineage changes including foveolar hyperplasia and spasmolytic polypeptide expressing metaplasia (SPEM) [3].

Anatomical context of DMP 777

Only approximately 5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile [4].
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 [3].

Gene context of DMP 777

Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys [4].

References

Reversible drug-induced oxyntic atrophy in rats. Goldenring, J.R., Ray, G.S., Coffey, R.J., Meunier, P.C., Haley, P.J., Barnes, T.B., Car, B.D. Gastroenterology (2000) [Pubmed]
Altered metaplastic response of waved-2 EGF receptor mutant mice to acute oxyntic atrophy. Ogawa, M., Nomura, S., Varro, A., Wang, T.C., Goldenring, J.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777. Ogawa, M., Nomura, S., Car, B.D., Goldenring, J.R. Dig. Dis. Sci. (2006) [Pubmed]
Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys. Vincent, S.H., Painter, S.K., Luffer-Atlas, D., Karanam, B.V., McGowan, E., Cioffe, C., Doss, G., Chiu, S.H. Drug Metab. Dispos. (1997) [Pubmed]
Degradation kinetics of DMP 777, an elastase inhibitor. Raghavan, K.S., Gray, D.B., Scholz, T.H., Nemeth, G.A., Hussain, M.A. Pharm. Res. (1996) [Pubmed]

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