iOWH-032(iOWH-032) - 药物靶点：CFTR_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

CFTR

作用机制

CFTR抑制剂(囊性纤维化跨膜传导调节因子抑制剂)

治疗领域

感染其他疾病

在研适应症-

非在研适应症

急性腹泻霍乱腹泻+ [1]

原研机构

Program for Appropriate Technology in Health

在研机构-

非在研机构

Program for Appropriate Technology in Health

PATH Drug Solutions

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C22H15Br2N3O4

InChIKeyDSFNLJXHXBIKDS-UHFFFAOYSA-N

CAS号1191252-49-9

关联

3

项与 iOWH-032 相关的临床试验

NCT04150250 / Completed临床2期IIT

A Phase 2a Randomized, Single-Center, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Preliminary Efficacy of Oral iOWH032 Against Cholera Diarrhea in a Controlled Human Infection Model

This trial was designed to assess safety and preliminary efficacy of oral doses of iOWH032 on diarrhea output and clinical symptoms after a cholera challenge in healthy adult participants.

开始日期2019-11-04

申办/合作机构

Program for Appropriate Technology in Health

[+2]

NCT02111304 / Withdrawn临床2期IIT

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Two-Part Trial to Evaluate the Efficacy, Safety, and Tolerability of iOWH032 in the Treatment of Acute Dehydrating Diarrhea in Adult and Pediatric Patients With Cholera

The primary hypothesis is that administration of iOWH032 to adult and pediatric males and females with acute cholera due to V. cholerae O1 reduces stool output in the first 24 hours significantly more than does the current standard of care.

开始日期2014-06-01

申办/合作机构

Program for Appropriate Technology in Health

[+1]

NCT01823939 / Completed临床1期IIT

Two-Part, Single-Centre Pharmacokinetic Study of iOWH032 in Adult Male and Female Healthy Volunteers, and Adult Males With Cholera

This study will assess if the pharmacokinetics, safety and tolerability of iOWH032 are grossly different in 1) Bangladeshi healthy population and 2) Bangladeshi cholera patients. This is not a hypothesis-driven research study.

开始日期2013-05-01

申办/合作机构

Program for Appropriate Technology in Health

100 项与 iOWH-032 相关的临床结果

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100 项与 iOWH-032 相关的转化医学

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100 项与 iOWH-032 相关的专利（医药）

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7

项与 iOWH-032 相关的文献（医药）

2024-07-19·ACS Chemical Biology

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

Article

作者: Zhang, Yingkai ; Lupoli, Tania J ; Chen, Eric ; Yang, Chao ; Desvignes, Ludovic ; Ciervo, Samantha ; Mulligan, Mark J ; Soper, Nathan ; Yardumian, Isabelle ; Oom, Aaron L

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains a clinically untapped target. Nsp13 is a helicase responsible for unwinding double-stranded RNA during viral replication and is essential for propagation. Like other helicases, Nsp13 has two active sites: a nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) and a nucleic acid binding channel that unwinds double-stranded RNA or DNA. Targeting viral helicases with small molecules, as well as the identification of ligand binding pockets, have been ongoing challenges, partly due to the flexible nature of these proteins. Here, we use a virtual screen to identify ligands of Nsp13 from a collection of clinically used drugs. We find that a known ion channel inhibitor, IOWH-032, inhibits the dual ATPase and helicase activities of SARS-CoV-2 Nsp13 at low micromolar concentrations. Kinetic and binding assays, along with computational and mutational analyses, indicate that IOWH-032 interacts with the RNA binding interface, leading to displacement of nucleic acid substrate, but not bound ATP. Evaluation of IOWH-032 with microbial helicases from other superfamilies reveals that it is selective for coronavirus Nsp13. Furthermore, it remains active against mutants representative of observed SARS-CoV-2 variants. Overall, this work provides a new inhibitor for Nsp13 and provides a rationale for a recent observation that IOWH-032 lowers SARS-CoV-2 viral loads in human cells, setting the stage for the discovery of other potent viral helicase modulators.

2016-08-01·American Journal of Physiology-Lung Cellular and Molecular Physiology2区 · 医学

Potentiators exert distinct effects on human, murine, andXenopusCFTR

2区 · 医学

Article

作者: Senderowitz, Hanoch ; Infield, Daniel T. ; Imhoff, Barry R. ; Cui, Guiying ; Khazanov, Netaly ; Stauffer, Brandon B. ; McCarty, Nael A.

VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.g., human, mouse, and Xenopus (frog). In the present study, we combined this comparative molecular pharmacology approach with that of computer-aided drug discovery to identify and characterize new potentiators of CFTR and to explore possible mechanism of action. Our results demonstrate that 1) VX-770, NPPB, GlyH-101, P1, P2, and P3 all exhibited ortholog-specific behavior in that they potentiated hCFTR, mCFTR, and xCFTR with different efficacies; 2) P1, P2, and P3 potentiated hCFTR in excised macropatches in a manner dependent on the degree of PKA-mediated stimulation; 3) P1 and P2 did not have additive effects, suggesting that these compounds might share binding sites. Also 4) using a pharmacophore modeling approach, we identified three new potentiators (IOWH-032, OSSK-2, and OSSK-3) that have structures similar to GlyH-101 and that also exhibit ortholog-specific potentiation of CFTR. These could potentially serve as lead compounds for development of new drugs for the treatment of cystic fibrosis. The ortholog-specific behavior of these compounds suggest that a comparative pharmacology approach, using cross-ortholog chimeras, may be useful for identification of binding sites on human CFTR.

2011-08-01·Future Medicinal Chemistry4区 · 医学

Developing Novel Antisecretory Drugs to Treat Infectious Diarrhea

4区 · 医学

Review

作者: Tue Nguyen ; Eugenio L de Hostos ; Robert K M Choy

Diarrhea, a disease of poverty and poor sanitation, kills an estimated two million children each year. Oral rehydration therapy is a very simple and inexpensive treatment that has significantly reduced mortality from secretory diarrhea caused by rotavirus, cholera and enterotoxigenic Escherichia coli. The efficacy and adoption of oral rehydration therapy would be enhanced by a drug that reduces fluid loss associated with these diseases and alleviates disease symptoms. Secretion and absorption by the intestine offer a number of potential drug targets to reduce fluid loss. Among these, the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most attractive because it is the primary driver of secretion in cases of diarrhea caused by enterotoxigenic bacteria. CFTR can be inhibited by both natural products and synthetic small molecules. iOWH032 is a synthetic CFTR inhibitor that has recently entered clinical trials for this indication.

100 项与 iOWH-032 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
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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
急性腹泻	临床2期	孟加拉国	Program for Appropriate Technology in Health	2014-06-01
霍乱	临床2期	孟加拉国	Program for Appropriate Technology in Health	2014-06-01
霍乱	临床2期	孟加拉国	Program for Appropriate Technology in Health	2014-06-01
分泌性腹泻	临床2期	孟加拉国	Program for Appropriate Technology in Health	2014-06-01
腹泻	临床2期	美国	PATH Drug Solutions	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04150250 (Pubmed \| PLoS Negl Trop Dis)	临床2期	霍乱	47	iOWH032	(選觸衊範蓋構夢繭繭廠) = 選膚積築憲醖壓鏇齋膚窪鏇憲壓網蓋簾繭醖網 (築淵膚壓壓壓繭鏇遞鏇, 8.9 ~ 58.3)	不佳	2021-11-18
				Placebo	(選觸衊範蓋構夢繭繭廠) = 衊餘壓繭餘獵鬱鑰廠遞窪鏇憲壓網蓋簾繭醖網 (築淵膚壓壓壓繭鏇遞鏇, 15.8 ~ 48.2)
NCT04150250 (CAST, CTgov)	临床2期	霍乱	47	Antibiotics+iOWH032 (iOWH032)	簾鹽憲願糧醖製鏇構廠(鬱範願衊蓋獵鹽廠築顧) = 醖憲糧鏇選網獵窪願觸壓顧糧鑰夢鹹糧夢襯衊 (鹽鏇觸憲製願膚構積顧, 糧繭鑰膚選選築鹽淵選 ~ 網窪願艱築鬱夢壓廠餘) 更多	-	2021-03-25
				Placebo (Placebo)	簾鹽憲願糧醖製鏇構廠(鬱範願衊蓋獵鹽廠築顧) = 窪範範壓遞壓鹹齋醖膚壓顧糧鑰夢鹹糧夢襯衊 (鹽鏇觸憲製願膚構積顧, 衊網簾鏇構網顧衊鬱鏇 ~ 網廠網鑰襯齋窪憲製鹽) 更多