DEVELOPMENT OF A NOVEL DRUG CANDIDATE WITH A FIRST-in-CLASS MECHANISM FOR SMOKING CESSATION, RELAPSE and ABSTINENCE
开发具有一流戒烟、复吸和戒烟机制的新型候选药物
基本信息
- 批准号:9788405
- 负责人:
- 金额:$ 215.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AbstinenceAddressAdvanced DevelopmentAffinityAgonistAnalytical ChemistryAnimal ModelBackBehavioralBupropionCanis familiarisCardiovascular systemCause of DeathChemicalsClinicalClinical Drug DevelopmentClinical ResearchClinical TrialsCountryCuesCyclic GMPDevelopmentDevelopment PlansDoseDrug KineticsExposure toFormulationFutureGene ClusterGenesGenetic PolymorphismGoalsHarm ReductionHumanHuman GeneticsIntakeInvestigationInvestigational DrugsLeadLegal patentLigandsLinkMaintenanceModelingMolecularMonkeysMorbidity - disease rateNicotineNicotine DependenceNicotinic ReceptorsOralOutcomePermeabilityPharmaceutical PreparationsPharmacologyPharmacotherapyPhasePlacebosPlayPopulationPositioning AttributePreparationProcessPropertyRattusRelapseReportingRiskRodentRoleRouteSafetySecureSelf AdministrationSeriesSmall Business Innovation Research GrantSmokerSmokingSmoking BehaviorSolubilityStressSubstance Use DisorderTelemetryTestingTherapeuticTobaccoTobacco useToxicologyValidationVomitingWithdrawalcardiovascular pharmacologyclinical developmentcravingdependence relapsedisorder later incidence preventiondrug candidatedrug discriminationdrug relapsegenetic associationgenome wide association studygenotoxicityimprovedin vivolead candidatelead optimizationmeetingsmethod developmentnanomolarnicotine replacementnicotine seeking behaviornonhuman primatenovelnovel strategiesnovel therapeuticsoff-patentphase I trialpre-clinicalpreclinical efficacypreventrespiratoryresponsesafety assessmentsafety studyscale upsmall moleculesmoking cessationsuccessvarenicline
项目摘要
ABSTRACT
This application, in response to PAR-18-219 `Grand Opportunity in Medications Development for
Substance-use Disorders', proposes to advance the IND-enabling development of a novel small-molecule drug
candidate with a novel first-in-class mechanism as pharmacotherapy for smoking cessation, relapse prevention
and longterm abstinence. Relapse to smoking is very common after initial abstinence with pharmacotherapy
and represents a major clinical challenge. 24-week abstinence rates for all three available pharmacotherapies
is still poor and averages only 22% for varenicline, 16% for bupropion, and 16% for nicotine replacement
therapies, compared to 9% for placebo. These poor abstinence rates with current pharmacotherapies are
inadequate for overall tobacco harm reduction, given that tobacco use still remains the leading preventable
cause of death and morbidity in the developed world. Despite the clear need and possible high impact, there
have been no new pharmacotherapy approved for smoking cessation for over a decade since varenicline's
approval. There is a crucial need for new approaches and new pharmacotherapy that reduce craving and
relapse and can promote sustained abstinence. This application aims to advance the IND development of a
novel pharmacotherapeutic with a new first-in-class mechanism for relapse prevention and smoking cessation,
that has shown distinctive preclinical efficacy in decreasing cue-induced, stress-induced and nicotine-induced
relapse and nicotine self-administration. The lead drug candidate is a new molecular entity targeting a new
pharmacological mechanism, the α3β4 nicotinic acetylcholine receptor (nAChR). The α3β4 nAChR clearly
plays a role in nicotine dependence and drug relapse mechanisms, and genome-wide association studies in a
large population of smokers reveal that polymorphisms in the genes encoding the α3, β4 and α5 subunits of
the nAChR are linked to increases in risk for nicotine dependence and inability to quit. The lead candidate
proposed for development is selected from a novel series of highly potent and selective α3β4 nAChR ligands,
which to our knowledge, are some of the most selective α3β4 nAChR ligands reported. Importantly, their
excellent in vivo efficacy for blocking reinstatement of nicotine seeking (a model of relapse), strongly suggests
that targeting the α3β4 nAChR may provide a superior profile over existing treatments, particularly for
improving longterm abstinence and preventing relapse. We have completed several preclinical toxicology and
DMPK studies that confirm the suitability of the lead candidate for IND-enabling studies. We propose to
continue the development and file an IND to enable the assessment of the safety and efficacy of this first-in-
class mechanism in human clinical trials. With our results thus far, we anticipate that we will be able to
advance the future clinical development of this drug candidate into a successful smoking cessation medication
and a safe effective option for quitting and sustaining long-term abstinence.
摘要
本申请是对PAR-18-219“药物开发的重大机遇”的回应,
物质使用障碍“,提出推进IND使能开发一种新型小分子药物
候选人与一个新的一流的机制作为药物治疗戒烟,复发预防
长期禁欲。药物治疗戒烟后复吸是很常见的
并且代表了主要的临床挑战。24-所有三种可用药物疗法的一周禁欲率
伐尼克兰平均只有22%,安非他酮平均只有16%,尼古丁替代品平均只有16
与安慰剂相比,安慰剂为9%。目前药物治疗的低戒烟率是
鉴于烟草使用仍然是可预防的主要疾病,
死亡和发病的原因。尽管有明确的需求和可能的高影响,
自从伐尼克兰的戒烟药物上市以来,
批准迫切需要新的方法和新的药物疗法来减少渴望,
复发,可以促进持续的禁欲。该申请旨在推进IND开发,
具有预防复发和戒烟的新机制的新型药物,
其在减少线索诱导的、应激诱导的和尼古丁诱导的
复发和尼古丁自我给药。先导候选药物是一种新的分子实体,
药理学机制,α3β4烟碱乙酰胆碱受体(nAChR)。α3β4 nAChR明显
在尼古丁依赖和药物复发机制中起作用,
大量吸烟者揭示了编码α3、β4和α5亚基基因多态性,
nAChR与尼古丁依赖和无法戒烟的风险增加有关。领先的候选人
从一系列新型高效和选择性α3β4 nAChR配体中选择,
据我们所知,这是一些报道的最具选择性的α3β4 nAChR配体。重要的是他们
阻断尼古丁寻求的恢复(复发模型)的极好的体内功效,强烈表明
靶向α3β4 nAChR可能提供优于现有治疗的上级特征,特别是对于
改善长期戒断和预防复发。我们已经完成了几项临床前毒理学研究,
DMPK研究,确认了IND使能研究的主要候选药物的适用性。我们建议
继续开发并提交IND,以评估这种首次临床试验的安全性和有效性。
类机制在人体临床试验。根据我们目前的结果,我们预计我们将能够
推进该候选药物的未来临床开发,使其成为成功的戒烟药物
也是戒烟和维持长期禁欲的安全有效选择。
项目成果
期刊论文数量(0)
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Nurulain T Zaveri其他文献
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{{ truncateString('Nurulain T Zaveri', 18)}}的其他基金
Development of Next-generation Pharmacotherapy for Opioid Use Disorders
开发治疗阿片类药物使用障碍的下一代药物疗法
- 批准号:
10680546 - 财政年份:2019
- 资助金额:
$ 215.88万 - 项目类别:
Development of Next-generation Pharmacotherapy for Opioid Use Disorders
开发治疗阿片类药物使用障碍的下一代药物疗法
- 批准号:
10655111 - 财政年份:2019
- 资助金额:
$ 215.88万 - 项目类别:
PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES
新型戒烟药物的临床前开发
- 批准号:
8715436 - 财政年份:2014
- 资助金额:
$ 215.88万 - 项目类别:
PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES
新型戒烟药物的临床前开发
- 批准号:
8848367 - 财政年份:2014
- 资助金额:
$ 215.88万 - 项目类别:
Development of Novel Drugs for Smoking Cessation Pharmacotherapy
戒烟药物治疗新药的开发
- 批准号:
8315565 - 财政年份:2012
- 资助金额:
$ 215.88万 - 项目类别:
A NOVEL APPROACH FOR PAIN TREATMENT WITHOUT OPIOID LIABILITIES
一种没有阿片类药物副作用的疼痛治疗新方法
- 批准号:
9270527 - 财政年份:2012
- 资助金额:
$ 215.88万 - 项目类别:
Analgesic Potential of NOP Agonists to Treat Pain in Sickle Cell Disease
NOP 激动剂治疗镰状细胞病疼痛的镇痛潜力
- 批准号:
8394806 - 财政年份:2012
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Development of Novel Therapies for Levodopa-induced Dyskinesia in Parkinson's Dis
帕金森病左旋多巴诱发的运动障碍新疗法的开发
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7927877 - 财政年份:2010
- 资助金额:
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8848273 - 财政年份:2009
- 资助金额:
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Discovery of Bifunctional NOP/Opioid Receptor Ligands for Drug Abuse Therapy
用于药物滥用治疗的双功能 NOP/阿片受体配体的发现
- 批准号:
7767102 - 财政年份:2009
- 资助金额:
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