PF-592379(PF-592379) - 药物靶点：D3 receptor_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

D3 receptor

作用机制

D3 receptor激动剂(多巴胺D3受体激动剂)

治疗领域

免疫系统疾病神经系统疾病皮肤和肌肉骨骼疾病+ [1]

在研适应症-

非在研适应症

勃起功能障碍骨关节炎疼痛

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-

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结构

分子式C13H21N3O

InChIKeyDFTCYTDJDXZFSK-JQWIXIFHSA-N

CAS号710655-15-5

关联

3

项与 PF-592379 相关的临床试验

NCT00483977 / Terminated临床2期

A 2 Week, Randomized, Double Blind, Placebo And Positive Controlled, Parallel Group, Multicentre Study To Assess The Efficacy And Tolerability Of PF-00592379 In Patients With Moderate To Severe Pain Due To Osteoarthritis

The primary aim is to assess if PF-00592379 is able to reduce pain in patients with osteoarthritis of the knee.

开始日期2007-06-01

申办/合作机构

Pfizer Inc.

EUCTR2005-004648-30-GB / Not yet recruiting临床2期

A randomized double blind, placebo controlled balanced 4-way crossover study to assess the efficacy of single oral doses of PF-00592379 on erectile function, using 100mg sildenafil as a positive control. - N/A

开始日期2006-02-02

申办/合作机构

Pfizer Ltd.

NCT00273416 / Completed临床2期

A Randomized Double Blind, Placebo Controlled Balanced 4-Way Crossover Study To Assess The Efficacy Of Single Oral Doses Of PF-00592379 On Erectile Function, Using 100mg Sildenafil As A Positive Control

The primary aim of this study is to assess how effective PF-00592379 is in restoring penile erections in patients with erectile dysfunction. Patients will attend for 4 treatment visits where they will receive the following in random order; 2 separate doses of PF-00592379, sildenafil 100mg used as a positive control, or placebo (dummy medication). The effect on penile erections will be assessed in the clinic using penile plethysmography (RigiScan PlusTM technique).

开始日期2006-01-01

申办/合作机构

Pfizer Inc.

100 项与 PF-592379 相关的临床结果

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100 项与 PF-592379 相关的转化医学

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100 项与 PF-592379 相关的专利（医药）

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5

项与 PF-592379 相关的文献（医药）

2024-08-09·ACS Pharmacology & Translational Science

Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors

Article

作者: Battiti, Francisco O. ; Lee, Kuo Hao ; Garland, Rian ; Bonifazi, Alessandro ; Yano, Hideaki ; Newman, Amy Hauck ; Jo, Yoon Jae ; Famiglietti, John ; Zhang, Wenqi ; Shi, Lei ; Semeano, Ana

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles in vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles. Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry through testing six distinct chirally resolved linkers and a simple aliphatic linker. The structure activity relationships (SARs) of these linkers are examined extensively, beyond the conventional level, by characterizing the activation of all putative transducers over a 44 min time course. Our multiparametric analysis reveals previously unappreciated specific linker-dependent effects on primary pharmacophores, receptors, transducer activation kinetics, and bias, highlighting the utility of this comprehensive approach and the significance of the linker type in shaping transducer bias profiles.

2019-07-11·Journal of Medicinal Chemistry1区 · 医学

The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D₃ Receptor (D₃R) Selective Agonists

1区 · 医学

Article

作者: Lam, Jenny ; Newman, Amy Hauck ; Slusher, Barbara S. ; Cemaj, Sophie L. ; Rais, Rana ; Shaik, Anver Basha ; Imler, Greg H. ; Deschamps, Jeffery R. ; Guerrero, Adrian M. ; Battiti, Francisco O. ; Bonifazi, Alessandro

Because of the large degree of homology among dopamine D₂-like receptors, discovering ligands capable of discriminating between the D₂, D₃, and D₄ receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D₃ preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D₃R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D₃R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D₃R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.

2012-06-01·Behavioural Pharmacology4区 · 心理学

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

4区 · 心理学

Article

作者: Paul Gupta ; Paul Butler ; Chris Wayman ; Gregory T. Collins ; S. Barak Caine ; Geoffrey Oberhofer ; Sian Ratcliffe

Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D3 agonist PF-592,379 to the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.

100 项与 PF-592379 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
骨关节炎	临床2期	美国	Pfizer Inc.	2007-06-01
勃起功能障碍	临床2期	挪威	Pfizer Inc.	2006-01-01
勃起功能障碍	临床2期	英国	Pfizer Inc.	2006-01-01
疼痛	临床2期	美国	Pfizer Inc.	-