KM-003(KM-003) - 药物靶点：ENaC_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [3]

靶点

ENaC

作用机制

ENaC阻滞剂(上皮细胞钠离子通道阻滞剂)

治疗领域

免疫系统疾病遗传病与畸形消化系统疾病+ [6]

在研适应症-

非在研适应症

支气管扩张支气管炎囊性纤维化+ [3]

原研机构

Parion Sciences, Inc.

在研机构-

非在研机构

Parion Sciences, Inc.

Kainos Medicine, Inc.

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C19H26ClN7O4

InChIKeyNTRKMGDUWYBLMS-UHFFFAOYSA-N

CAS号587879-32-1

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关联

3

项与 KM-003 相关的临床试验

NCT01369589 / Completed临床1/2期

An Evaluation of the Impact of a Single Dose of P-552 on Oral Mucosal Wetness in Subjects With Xerostomia Related to Sjogren's Syndrome

The primary objective of this clinical study is to determine the impact of P-552 oral rinse on salivary volume after administration of a single dose of P-552and versus vehicle rinse. Changes in oral mucosal wetness will be assessed via collection of salivary output and via measurement of oral wetness using the Periotron 8000 instrument.

开始日期2010-11-01

申办/合作机构

Parion Sciences, Inc.

NCT00852839 / Completed临床2期

A Randomized, Double-Blind, Vehicle-Controlled, Parallel Arm Study of 552-02 in Subjects With Dry Mouth Associated With Sjogren's Syndrome

This clinical study is to determine whether daily administration of a formulation of 552-02 improves the dry mouth condition in subjects with primary Sjögren's syndrome.

开始日期2009-02-01

申办/合作机构

Parion Sciences, Inc.

NCT00274313 / Completed临床1/2期

A Study of the Safety and Pharmacokinetics of 552-02 Following 14 Days of Dosing By Inhalation in Patients With Cystic Fibrosis

The purpose of this study is to evaluate the safety and tolerability of a new inhaled sodium-channel blocker called 552-02 in teens and adults with cystic fibrosis. 552-02 will be inhaled once a day for 14 days using a nebulizer. A small subgroup of patients will donate blood samples for pharmacokinetic analysis to see how 552-02 is absorbed into the blood and eliminated after 14 days of treatment.

开始日期2006-01-01

申办/合作机构

Parion Sciences, Inc.

100 项与 KM-003 相关的临床结果

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100 项与 KM-003 相关的转化医学

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100 项与 KM-003 相关的专利（医药）

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3

项与 KM-003 相关的文献（医药）

2008-12-01·British Journal of Pharmacology2区 · 医学

The guinea‐pig tracheal potential difference as an in vivo model for the study of epithelial sodium channel function in the airways

2区 · 医学

Article

作者: Henry Danahay ; Martin Gosling ; Hazel Atherton ; Nicola Smith ; Alice Young ; Rachel Burrows ; Paul Groot-Kormelink ; Jean-Marc Schlaeppi ; Rosemary Sugar ; Kevin Coote

Background and purpose:The epithelial sodium channel (ENaC) is a key regulator of airway mucosal hydration and mucus clearance. Negative regulation of airway ENaC function is predicted to be of clinical benefit in the cystic fibrosis lung. The aim of this study was to develop a small animal model to enable the direct assessment of airway ENaC function in vivo.Experimental approach:Tracheal potential difference (TPD) was utilized as a measure of airway epithelial ion transport in the guinea‐pig. ENaC activity in the trachea was established with a dose–response assessment to a panel of well‐characterized direct and indirect pharmacological modulators of ENaC function, delivered by intra‐tracheal (i.t.) instillation.Key results:The TPD in anaesthetized guinea‐pigs was attenuated by the direct ENaC blockers: amiloride, benzamil and CF552 with ED50 values of 16, 14 and 0.2 μg kg−1 (i.t.), respectively. 5‐(N‐Ethyl‐N‐isopropyl) amiloride, a structurally related compound but devoid of activity on ENaC, was without effect on the TPD. Intra‐tracheal dosing of the Kunitz‐type serine protease inhibitors aprotinin and placental bikunin, which have previously been demonstrated to inhibit proteolytic activation of ENaC, likewise potently attenuated TPD in guinea‐pigs, whereas α1‐antitrypsin and soya bean trypsin inhibitor were without effect.Conclusions and implications:The pharmacological sensitivity of the TPD to amiloride analogues and also to serine protease inhibitors are both consistent with that of ENaC activity in the guinea‐pig trachea. The guinea‐pig TPD therefore represents a suitable in vivo model of human airway epithelial ion transport.British Journal of Pharmacology (2008) 155, 1025–1033; doi:10.1038/bjp.2008.363; published online 22 September 2008

2008-04-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Pharmacological Properties ofN-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease

3区 · 医学

Article

作者: William M. Abraham ; Boyoung Cha ; Jacquelyn Fleegle ; M. Ross Johnson ; Kevin B. Johnson ; Mark Donowitz ; Ray A. Caldwell ; Juan R. Sabater ; William R. Thelin ; Jim Zhang ; Richard C. Boucher ; Andrew J. Hirsh ; Andra Zamurs ; Judith A. St. George

Amiloride improves mucociliary clearance (MC) by blocking airway epithelial sodium channels (ENaC) and expanding airway surface liquid (ASL). However, the low potency and rapid absorption of amiloride by airway epithelia translated into a short duration of efficacy as an aerosolized therapy for cystic fibrosis (CF) patients. To improve ENaC blocker CF pharmacotherapy, a more potent and durable ENaC blocker tailored for aerosol delivery was synthesized. Parion compound N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02) was tested for potency and reversibility of ENaC block, epithelial absorption and biotransformation, selectivity, durability of ASL expansion under isotonic and hypertonic conditions in canine and human CF bronchial epithelial cells, and drug dissociation on ENaC in Xenopus oocytes. Short-circuit current assessed compound potency and reversibility, patch-clamp recordings of ENaC current assessed drug off-rate (k(off)), a gravimetric method and confocal microscopy measured mucosal water retention and ASL height, and drug absorption and biotransformation were assessed using liquid chromatography-mass spectrometry. Amiloride and 552-02 were tested in vivo for MC activity in sheep immediately and 4 to 6 h after aerosol dosing. Compared with amiloride, compound 552-02 was 60 to 100-fold more potent, it was 2 to 5-fold less reversible, it was slower at crossing the epithelium, and it exhibited a 170-fold slower k(off) value. 552-02 exhibited greater ASL expansion over 8 h in vitro, and it was more effective than amiloride at increasing MC immediately and 4 to 6 h after dosing. When combining hypertonic saline and 552-02, a synergistic effect on ASL expansion was measured in canine or CF bronchial epithelia. In summary, the preclinical data support the clinical use of 552-02 +/- hypertonic saline for CF lung disease.

1986-10-01·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Distinct human leukemia-associated cell surface glycoprotein GP160 defined by monoclonal antibody SN6.

1区 · 综合性期刊

Article

作者: Seon, Ben K. ; Haruta, Yuro

In this study, a monoclonal antibody (mAb) termed SN6 was generated by immunizing a mouse with a non-T-cell leukemia antigen preparation isolated from cell membranes of leukemia cells derived from a patient (FJ) with non-T/non-B-cell-type acute lymphoblastic leukemia (ALL). SN6 was tested against a variety of cultured and uncultured human cell specimens by using a sensitive cellular radioimmunoassay. Among the 26 cultured malignant and nonmalignant cell lines tested, SN6 reacted with all of the 6 leukemic non-T/non-B (including pre-B)-cell lines tested--i.e., KM-3, NALM-16, REH, NALL-1, NALM-1, and NALM-6. Of these cell lines, 5 were derived from individual patients with ALL; the remaining 1 was from a patient with chronic myelocytic leukemia in blast crisis. In addition, SN6 reacted with 3 of 3 leukemic myelo-monocytic cell lines tested--i.e., ML-2, HL-60, and U937. SN6 did not react with any other cell lines. A consistent result was obtained with 42 fresh (uncultured) cell specimens derived from individual patients with several different types of leukemias. SN6 reacted with 11 of 16 non-T/non-B (including pre-B)-cell ALL specimens. In addition, it reacted with various myelo-monocytic leukemia cell specimens to various degrees. SN6 did not show a significant reaction with normal peripheral blood cells tested, which included B cells, T cells, granulocytes, monocytes, and erythrocytes. However, it reacted with a small population (approximately 1% as determined by immunofluorescence staining) of normal bone marrow cells. The approximate molecular mass of the glycoprotein antigen defined by SN6 was determined to be 160,000 by radioimmunoprecipitation followed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Only one component of 80,000 daltons was formed upon reduction of the 160,000 molecular mass antigen. Therefore, this antigen is apparently a homodimer of a 80,000-dalton subunit. This conclusion was further corroborated by two-dimensional gel analysis, which showed a single well-defined spot for the reduced antigen. We designate this distinct human leukemia-associated cell surface antigen "GP160."

100 项与 KM-003 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
支气管扩张	临床2期	美国	Parion Sciences, Inc.	-
支气管炎	临床2期	美国	Parion Sciences, Inc.	-
囊性纤维化	临床2期	-	Kainos Medicine, Inc.	-
囊性纤维化	临床2期	美国	Parion Sciences, Inc.	-
慢性阻塞性肺疾病	临床2期	美国	Parion Sciences, Inc.	-
辐射损伤	临床2期	美国	Parion Sciences, Inc.	-
干燥综合征	临床2期	-	Kainos Medicine, Inc.	-
干燥综合征	临床2期	-	Kainos Medicine, Inc.	-