DMP 777 is a potent, selective, and orally active human leukocyte elastase (HLE) inhibitor. Human leukocyte elastase (HLE)[2]
DMP-777-treated rats show a marked decrease in H/K-ATPase staining parietal cells. DMP-777-induced loss of parietal cells is significantly ameliorated with coadministration of omeprazole. DMP-777-treated animals demonstrates marked foveolar hyperplasia in the fundus with prominent expansion of diastase-resistant, PAS-positive surface mucous cells. When DMP-777 is coadministeredwith omprazole, there is a significant decrease in BrdUpositive S-phase cells compared with rats thatreceive DMP-777 alone[1]. After oral dosing of monkeys at 40 mg/kg with DMP-777 the only stereoisomer detected in the post-dose plasma samples is the starting material DMP-777, and no inversion of the configuration at positions 'a' and 'b' of DMP-777 has occurred in vivo[2]. Mist1-/- mice treated with DMP-777 show fewer chief cell to SPEM transitions. Mist1-/- mice treated with L635 demonstrates significantly fewer proliferative SPEM cells compared to control mice[3].
[1]. Ogawa M, et al. Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777. Dig Dis Sci. 2006 Mar;51(3):431-9. [2]. Zagrobelny J, et al. Separation of the four stereoisomers of a potent inhibitor (L-694,458) of human leukocyte elastase and its determination in human plasma using achiral/chiral chromatography with column switching. J Pharm Biomed Anal. 1998 Sep 1;17(6-7 [3]. Weis VG, et al. Maturity and age influence chief cell ability to transdifferentiate into metaplasia. Am J Physiol Gastrointest Liver Physiol. 2016 Nov 23:ajpgi.00326.2016