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BioAssay: AID 274437

Agonist activity at human D4.4 receptor in HEK293 cells coexpressing G-alpha-qo5 by FLIPR

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship more ..
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 Tested Compounds
 Tested Compounds
All(71)
 
 
Active(70)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(71)
 
 
Active(70)
 
 
Unspecified(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 274437
Data Source: ChEMBL (422463)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-25
Modify Date: 2014-05-23

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=D(4) dopamine receptor; AltName: Full=D(2C) dopamine receptor; AltName: Full=Dopamine D4 receptor
Description ..   
Protein Family: FAM101 family
Comment ..   

Gene:DRD4     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 70
Description:
Title: Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.

Abstract: The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
(PMID: 17149874)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment
Assay Type: Functional

Assay Data Source: Scientific Literature

BAO: Assay Format: cell-based format

Assay Cell Type: HEK293

Target Type: Target is a single protein chain

Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1EC50*EC50 PubChem standard valueFloatμM
2EC50 activity commentEC50 activity commentString
3EC50 standard flagEC50 standard flagInteger
4EC50 qualifierEC50 qualifierString
5EC50 published valueEC50 published valueFloatnM
6EC50 standard valueEC50 standard valueFloatnM
7EC50 binding domainsEC50 binding domainsString
8Efficacy activity commentEfficacy activity commentString
9Efficacy standard flagEfficacy standard flagInteger
10Efficacy qualifierEfficacy qualifierString
11Efficacy published valueEfficacy published valueFloat%
12Efficacy standard valueEfficacy standard valueFloat%
13Efficacy binding domainsEfficacy binding domainsString

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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