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Dexloxiglumide Sale

(Synonyms: 右氯谷胺) 目录号 : GC35846

A CCK1 receptor antagonist

Dexloxiglumide Chemical Structure

Cas No.:119817-90-2

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产品描述

Dexloxiglumide is a cholecystokinin (CCK) receptor antagonist and is the single (R) isomer of loxiglumide .1,2 It selectively binds to the CCK1 receptor over CCK2 in CHO cells expressing the rat receptors (Kis = 0.0234 and 5.88 ?M, respectively).1 Dexloxiglumide (20 ?mol/kg) inhibits guinea pig gallbladder contractions induced by the CCK agonist CCK octapeptide (sulfated) . It reduces CCK-8-induced gastric emptying in rats (ID50 = 1.14 mg/kg).2

1.Morton, M.F., Barrett, T.D., Yan, W., et al.3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a novel, potent, and selective cholecystokinin 1 receptor antagonist: In vitro and in vivo pharmacological comparison with dexloxiglumideJ. Pharmacol. Exp. Ther.323(2)562-569(2007) 2.Scarpignato, C., Kisfalvi, I., D'Amato, M., et al.Effect of dexloxiglumide and spiroglumide, two new CCK-receptor antagonists, on gastric emptying and secretion in the rat: Evaluation of their receptor selectivity in vivoAliment. Pharmacol. Ther.10(3)411-419(1996)

Chemical Properties

Cas No. 119817-90-2 SDF
别名 右氯谷胺
Canonical SMILES O=C(O)CC[C@@H](NC(C1=CC=C(Cl)C(Cl)=C1)=O)C(N(CCCOC)CCCCC)=O
分子式 C21H30Cl2N2O5 分子量 461.38
溶解度 DMSO: 50 mg/mL (108.37 mM) 储存条件 Store at -20°C
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Research Update

Dexloxiglumide for the treatment of constipation predominant irritable bowel syndrome

Expert Opin Pharmacother 2016 Oct;17(14):1969-74.PMID:27590736DOI:10.1080/14656566.2016.1229306.

Introduction: Irritable bowel syndrome (IBS) is a multifactorial functional gut disorder, where sensory/motor disturbances seem to play a major role, with no satisfactory treatment for a majority of patients. Cholecystokinin (CCK) is a hormone with several effects on gastrointestinal function, and IBS patients have been shown to produce altered sensory/motor responses to CCK. Areas covered: Dexloxiglumide is a selective antagonist of the type 1 receptor of CCK, which has demonstrated to revert the CCK mediated effects on gastrointestinal motility and sensitivity. In humans, Dexloxiglumide has been shown to accelerate gastric emptying, slow down transit in the proximal colon, and increase the tolerance to intestinal gas. In phase 2 clinical trials Dexloxiglumide 200 mg tid has demonstrated to be superior to placebo in symptom relief in constipation predominant IBS (IBS-C). In a phase 3 withdrawal study Dexloxiglumide obtained a more sustained effect than placebo. However, these promising effects in IBS-C have not been confirmed in large phase 3 studies so far. Expert opinion: Dexloxiglumide has demonstrated positive effects on important aspects of gastrointestinal function, like gastric emptying and gas tolerance, that deserves consideration in future studies. However, the available data is insufficient to recommend Dexloxiglumide for treatment of IBS-C today.

Pharmacokinetic profile of Dexloxiglumide

Clin Pharmacokinet 2006;45(12):1177-88.PMID:17112294DOI:10.2165/00003088-200645120-00003.

Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK1) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders. In female patients with constipation-predominant IBS, clinical efficacy has been demonstrated following administration of Dexloxiglumide 200 mg three times daily. Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition, Dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg. Dexloxiglumide absorption window extends from the jejunum to the colon and the drug is a substrate and a weak inhibitor of P-glycoprotein and multidrug resistance protein 1. Plasma protein binding of Dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans. Systemic clearance of Dexloxiglumide is moderate and cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of Dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to Dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of Dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the drug is a single isomer chiral drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged Dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. As the kidney is a minor contributor to the elimination of Dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency. The pharmacokinetics of Dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of Dexloxiglumide but severe liver impairment causes increases in systemic exposure to Dexloxiglumide and O-demethyl Dexloxiglumide. Thus, the drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of Dexloxiglumide.

Dexloxiglumide Rotta Research Lab

Curr Opin Investig Drugs 2002 Apr;3(4):621-6.PMID:12090734doi

Dexloxiglumide, the (R)-isomer of loxiglumide, is a selective and highly potent CCK1 receptor antagonist. It is twice as potent as the racemic compound. because the anti-CCK activity is specific to the (R)-form, whereas the (S)-isomer is almost ineffective. It has been developed by Rotta Research Lab SpA for the treatment of diseases in which CCK1 receptor activity is potentially involved, including gastrointestinal motility, food intake and pancreatic disorders [218696]. Its receptor-mediated actions have been described in multiple in vitro and in vivo pharmacological systems. Results from both preclinical and clinical studies indicate that it is an effective inhibitor of gallbladder contraction, improves lower esophegal sphincter (LES) function, accelerates gastric emptying, accelerates colonic transit and significantly decreases symptoms in IBS and functional dyspepsia patients, and therefore has potential as an effective treatment for constipation-predominant IBS. functional dyspesia, constipation, LES function, gastric emptying disorders and biliary colics. Forest Laboratories has entered into an agreement with Rotta for the development and marketing of Dexloxiglumide for the treatment of constipation-predominant IBS and phase III studies are currently ongoing in the US. In August 2000, Merrill Lynch expected that Dexloxiglumide would not be launched until 2004 [379892], and in June 2001, predicted a US filing date in 2003 [413928].

Characterization of Dexloxiglumide in vitro biopharmaceutical properties and active transport

J Pharm Sci 2003 Oct;92(10):1968-80.PMID:14502537DOI:10.1002/jps.10428.

The objective of this work was to characterize Dexloxiglumide biopharmaceutical properties in vitro and relate these characteristics to its in vivo absorption performance, and to assess Dexloxiglumide interaction with P-glycoprotein (P-gp) and MRP1 to anticipate its drug interaction potential. Dexloxiglumide aqueous solubility was moderate and pH dependent. Dexloxiglumide exhibited moderate Caco-2 permeability that was polarized, concentration dependent, and pH dependent. The apical-to-basolateral (AP-BL) permeability at pH 5 [14.5 (+/-1.8) x 10(-6) cm/s] was 2-fold higher than at pH 7.5 [7.24 (+/-0.27) x 10(-6) cm/s]. Neutral and ionized Dexloxiglumide species displayed permeabilities of 30.8 (+/-8.4) x 10(-6) cm/s and 9.03 (+/-1.31) x 10(-6) cm/s, respectively. The transport of Dexloxiglumide across MDR1-MDCK (P-gp overexpressing Madine Darby canine kidney cells) monolayers was polarized, with a BL-AP/AP-BL permeability ratio of 9.35 (+/-0.73), which was reduced to 1.03 (+/-0.03) by P-gp inhibition. Rhodamine 123 efflux was reduced by Dexloxiglumide from 4.06 (+/-0.34) to 2.84 (+/-0.15) across Caco-2 monolayers, and from 17.3 (+/-0.9) to 8.26 (+/-1.38) across MDR1-MDCK monolayers, further indicating Dexloxiglumide interaction with P-gp. Additionally, P-gp ATPase activity increased with Dexloxiglumide concentration. Dexloxiglumide was effluxed from MRP1-NIH3T3 cells (NIH-3T3 cells expressing the multidrug resistance-associated protein 1). Dexloxiglumide increased MRP1-substrate fluorescein uptake 4-fold, and fluorescein increased Dexloxiglumide uptake 1.8-fold. Overall, in vitro transport studies indicate Dexloxiglumide to be moderately soluble and moderately permeable, which is in agreement with the incomplete oral absorption of Dexloxiglumide. In vitro, Dexloxiglumide was moderately modulated by P-gp and MRP1, which provides a rationale for the design of drug interaction studies.

Effect of multiple-dose Dexloxiglumide on the pharmacokinetics of oral contraceptives in healthy women

J Clin Pharmacol 2005 Mar;45(3):329-36.PMID:15703367DOI:10.1177/0091270004272732.

This study was undertaken to evaluate the effect of Dexloxiglumide, a selective cholecystokinin receptor antagonist, on the pharmacokinetics of a combination oral contraceptive (OC). A single-blind, placebo-controlled, 2-period crossover study was conducted in 24 healthy young female subjects who received Ortho Tri-Cyclen containing ethinyl estradiol (EE, 0.035 mg) and norgestimate (NE, 0.180 mg/0.215 mg/0.250 mg per 7-day phase, respectively) for 5 days (days 17-21) concurrently with either 200 mg Dexloxiglumide (3 times a day on days 17-20, followed by a single dose on day 21) or matching placebo during 2 consecutive 28-day OC dosing cycles. Plasma was sampled up to 24 hours for the determination of EE, NE, and 17-deactyl norgestimate (17-DNE, a rapidly formed pharmacologically active metabolite of NE). The geometric mean ratios (GMRs, Dexloxiglumide/placebo) of the plasma concentration-time curve over 24 hours with corresponding 90% confidence intervals (CIs) for EE and 17-DNE were 1.21 (1.17-1.26) and 0.92 (0.89-0.95), respectively. The GMRs (90% CI) of C(max) for EE and 17-DNE were 1.15 (1.09-1.20) and 0.93 (0.90-0.96), respectively. Coadministration of OC and Dexloxiglumide was well tolerated and safe. Comparable systemic exposure of EE and 17-DNE in the presence and absence of Dexloxiglumide suggests that Dexloxiglumide treatment is unlikely to interfere with the safety and efficacy of oral contraceptives based on the analysis of the resulting pharmacokinetic profile.