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(Synonyms: (2S)-N-[(1R)-1-(1,3-苯并二氧戊环-5-基)丁基]-3,3-二乙基-2-[4-[(4-甲基-1-哌嗪基)羰基]苯氧基]-4-氧代-1-氮杂环丁烷甲酰胺,L-694458) 目录号 : GC35884

DMP 777 是一种有效的,选择性的,可口服的 human leukocyte elastase (HLE) 抑制剂。

DMP 777 Chemical Structure

Cas No.:157341-41-8

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,674.00
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5mg
¥1,350.00
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10mg
¥2,160.00
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25mg
¥4,590.00
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50mg
¥7,335.00
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200mg 待询 待询

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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Animal experiment:

Groups 1A and 1B receive control vehicle instead of omeprazole and DMP-777. Group 2A and 2B are dosed with DMP-777 once daily on Study Day 3 or Days 3 and 4, respectively, and receive control vehicle instead of omeprazole. Groups 3A and 3B are treated with omeprazole twice daily on Study Days 1 to 3 or Days 1 to 4, respectively, and receive control vehicle instead of DMP-777. Groups 4A and 4B are dosed with both omeprazole and DMP-777. On Study Days 1 and 2, animals are pretreated with omeprazole twice daily, the dosing intervals separated by approximately 6 hr. On Study Day 3 (Group 4A) or Days 3 and 4 (Group 4B), omeprazole is coadministered with DMP-777. The first dose of omeprazole is administered approximately 1 hr prior to the dose of DMP-777. The second dose is approximately 6 hr after the last dose of DMP-777. Groups 1A, 2A, 3A, and 4A are sacrificed on Day 4. Groups 1B, 2B, 3B, and 4B are sacrificed on Day 5. Bromodeoxyuridine (BrdU) is administered by intraperitoneal injection to all the rats, 2 hr prior to necropsy.

References:

[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

产品描述

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

Chemical Properties

Cas No. 157341-41-8 SDF
别名 (2S)-N-[(1R)-1-(1,3-苯并二氧戊环-5-基)丁基]-3,3-二乙基-2-[4-[(4-甲基-1-哌嗪基)羰基]苯氧基]-4-氧代-1-氮杂环丁烷甲酰胺,L-694458
Canonical SMILES CCC[C@H](C1=CC2=C(C=C1)OCO2)NC(N3[C@H](C(CC)(C3=O)CC)OC4=CC=C(C=C4)C(N5CCN(CC5)C)=O)=O
分子式 C31H40N4O6 分子量 564.67
溶解度 DMSO: 38.33 mg/mL (67.88 mM); Water: < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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1 mM 1.7709 mL 8.8547 mL 17.7095 mL
5 mM 0.3542 mL 1.7709 mL 3.5419 mL
10 mM 0.1771 mL 0.8855 mL 1.7709 mL
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Research Update

Degradation kinetics of DMP 777, an elastase inhibitor

Pharm Res 1996 Dec;13(12):1815-20.PMID:8987077DOI:10.1023/a:1016076907072.

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.

Isolation and identification of a degradation product in a capsule formulation containing the elastase inhibitor, DMP 777

J Pharm Biomed Anal 2001 Feb;24(4):651-7.PMID:11272322DOI:10.1016/s0731-7085(00)00461-1.

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.

Reversible drug-induced oxyntic atrophy in rats

Gastroenterology 2000 Jun;118(6):1080-93.PMID:10833483DOI:10.1016/s0016-5085(00)70361-1.

Background & aims: Oxyntic atrophy is the hallmark of chronic gastritis. Many studies have sought to develop animal models for oxyntic atrophy, but none of them are reversible. We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy. Methods: DMP 777 was administered to CD-1 rats by oral gavage (200 mg. kg(-1). day(-1)). Serum gastrin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. 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. Results: Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 inhibited aminopyrine accumulation into rabbit parietal cells stimulated with either histamine or forskolin. DMP 777 reversed a stimulated proton gradient in isolated parietal cell tubulovesicles. Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa. In response to the acute loss of parietal cells, there was an increase in the activity of the progenitor zone along with rapid expansion of the foveolar cell compartment. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of fundic glands. With extended dosing over 3-6 months, foveolar hyperplasia and oxyntic atrophy were sustained while chief cell, enterochromaffin-like cell, and somatostatin cell populations were decreased. No histological evidence of neoplastic transformation was observed with dosing up to 6 months. Withdrawal of the drug after 3 or 6 months of dosing led to complete restitution of the normal mucosal lineages within 3 months. Conclusions: DMP 777 acts as a protonophore with specificity for parietal cell acid-secretory membranes. DMP 777 in high doses leads to the specific loss of parietal cells. Foveolar hyperplasia, loss of normal gland lineages, and the emergence of basal mucous cells appear as sequelae of the absence of parietal cells. The results suggest that parietal cells are critical for the maintenance of the normal mucosal lineage repertoire.

Enantioselective allylation of imines catalyzed by newly developed (-)-β-pinene-based π-allylpalladium catalyst: an efficient synthesis of (R)-α-propylpiperonylamine and (R)-pipecolic acid

Org Biomol Chem 2012 Oct 14;10(38):7789-800.PMID:22910971DOI:10.1039/c2ob26188j.

A newly developed π-allylpalladium with a (-)-β-pinene framework and an isobutyl side chain catalyzed the enantioselective allylation of imines in good yields and enantioselectivities (20 examples, up to 98% ee). An efficient enantioselective synthesis of the (R)-α-propyl piperonylamine part of DMP 777, a human leukocyte elastase inhibitor and (R)-pipecolic acid have been achieved as a useful application of this methodology.