(CP-601927) - 药物靶点：Muscle-type nAChRs_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Muscle-type nAChRs

作用机制

Muscle-type nAChRs激动剂(肌肉型烟碱乙酰胆碱受体复合体激动剂)

治疗领域

其他疾病

在研适应症-

非在研适应症

重度抑郁症

原研机构

Pfizer Inc.

在研机构-

非在研机构

Pfizer 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-

结构

分子式C12H12F3N

InChIKeyRNOBTWYQAWEZHH-JGVFFNPUSA-N

CAS号357425-02-6

关联

2

项与 CP-601927 相关的临床试验

NCT01396135 / Withdrawn临床1期

A Phase 1, Randomized, Subject- And Investigator-blind, Sponsor-open, Placebo-controlled, Single- And Multiple-dose Study To Investigate The Pharmacokinetics, Safety And Tolerability Of Cp-601,927 In Healthy Japanese Subjects

This Phase 1 study is the first clinical trial to be conducted in Japanese subjects. The pharmacokinetics, safety and tolerability of single and multiple doses of CP-601,927 will be evaluated in Japanese, healthy, non-smoking subjects.

开始日期2011-08-26

申办/合作机构

Pfizer Inc.

NCT01098240 / Terminated临床2期

A RANDOMIZED PHASE 2A, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF CP-601,927 AUGMENTATION OF ANTIDEPRESSANT THERAPY IN MAJOR DEPRESSION

The primary objectives of this study are to: 1) Evaluate the efficacy of CP 601,927 compared to placebo in the augmentation of antidepressant therapy (ADT) in patients with Major Depressive Disorder (MDD) using the Montgomery Asberg Depression Rating Scale (MADRS). 2) Evaluate the safety and tolerability of CP 601,927 in patients with MDD on ADT.

开始日期2010-06-14

申办/合作机构

Pfizer Inc.

100 项与 CP-601927 相关的临床结果

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100 项与 CP-601927 相关的转化医学

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100 项与 CP-601927 相关的专利（医药）

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4

项与 CP-601927 相关的文献（医药）

2018-09-01·Psychopharmacology3区 · 医学

The contribution of agonist and antagonist activities of α4β2* nAChR ligands to smoking cessation efficacy: a quantitative analysis of literature data

3区 · 医学

Review

作者: Hurst, Raymond S ; Rollema, Hans

RATIONALE AND OBJECTIVETwo mechanisms underlie smoking cessation efficacies of α4β2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking.METHODSFunctional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4β2 nAChR, as well as at α6β2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist.RESULTSComparisons with odds ratios at end of treatment suggest that extensive α4β2 and α6β2* nAChR desensitization combined with α6β2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4β2 and α6β2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4β2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932).CONCLUSIONThree pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6β2* nAChRs, desensitization of α4β2 and α6β2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4β2 and α6β2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4β2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).

2015-02-01·Journal of Clinical Psychopharmacology4区 · 医学

Is There a Relationship to Leptin Levels?

4区 · 医学

Article

作者: Ramey, Tanya ; Fava, Maurizio ; Kinrys, Gustavo ; Boyer, Stacey ; Pickering, Eve ; Altstiel, Larry

This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4β2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14. There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo (least square mean difference [80% confidence interval], -1.30 [-3.32-0.71]). Post hoc analyses revealed that the drug-placebo difference in change from baseline (SE) to week 14 in MADRS score was greater in subjects with body mass index (BMI) less than or equal to 35 kg/m (-3.43 [1.87], P = 0.069) than those with BMI greater than 35 kg/m (3.37 [2.8], P = 0.230). Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome. P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055, respectively. CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs. However, post hoc analyses suggest that BMI, particularly elevated leptin levels, may have affected the response to CP-601,927; however, further study may be needed to confirm these results.

2013-09-01·Neuropharmacology2区 · 医学

Therapeutic doses of antidepressants are projected not to inhibit human α4β2 nicotinic acetylcholine receptors

2区 · 医学

Article

作者: Mark L. Weber ; Raymond S. Hurst ; Gunnar Flik ; Christopher L. Shaffer ; Corry M. Hofland ; Hans Rollema ; Thomas Cremers

Inhibition of central α4β2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations (Cu,b) at therapeutic doses with concentrations that inhibit human α4β2 nAChRs in vitro. Inhibitory concentrations (IC50) were determined by patch clamp and ranged from 0.8-3.2 μM, except for nortriptyline (IC50 = 100 nM). Cu,b values were calculated from human unbound plasma drug concentrations (Cu,p) and rat-derived brain-to-plasma and extracellular fluid-to-plasma ratios for the unbound drug, which are near unity, due to much higher brain tissue binding than plasma protein binding of these drugs. Accordingly in humans, antidepressant Cu,b are projected to essentially equal Cu,p, with average values from 3-87 nM, which are 30-to-250-fold below their IC50 concentrations. Based on our model, monoaminergic antidepressants minimally inhibit central nAChRs and it is unlikely that α4β2 nAChR antagonism contributes to their antidepressant activity. Nortriptyline is an exception with a Cu,b that is 2-fold below its IC50, which is comparable to the nAChR antagonist (±)-mecamylamine, for which Cu,b is 4-fold below its IC50; both drugs will inhibit a substantial fraction of α4β2 nAChRs. The Cu,b of the α4β2 nAChR partial agonist varenicline, which has antidepressant-like activity in a murine model, is higher than its IC50 and varenicline is projected to cause ~70% inhibition of α4β2 nAChRs. Taken together these data may help explain the negative outcome of recent antidepressant augmentation trials with mecamylamine and the partial agonist CP-601927.

100 项与 CP-601927 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12244

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
重度抑郁症	临床2期	美国	Pfizer Inc.	2010-06-14

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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


NCT01098240 (CTgov)	临床2期	重度抑郁症	297	CP-601,927 (CP-601,927 + ADT)	膚淵夢鹽鏇構獵繭襯憲(製襯繭鹹鏇夢願簾齋範) = 製鹽製遞製築繭願繭構鑰鏇鬱顧鬱憲醖窪鹽築 (構鹹選繭願醖壓遞築窪, 憲襯簾壓觸艱鹹製憲艱 ~ 觸鹹艱鏇鑰窪觸獵壓選) 更多	-	2013-06-26
				Placebo (Placebo + ADT)	膚淵夢鹽鏇構獵繭襯憲(製襯繭鹹鏇夢願簾齋範) = 遞齋積製網繭糧衊選構鑰鏇鬱顧鬱憲醖窪鹽築 (構鹹選繭願醖壓遞築窪, 艱鑰製獵鹽夢淵鏇壓選 ~ 觸鹽願構鏇網淵糧廠鹹) 更多