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BioAssay: AID 274441

Agonist activity at ferret D4 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(4)
 
 
Active(4)
 
 
 Tested Substances
 Tested Substances
All(4)
 
 
Active(4)
 
 
 Related BioAssays
 Related BioAssays
AID: 274441
Data Source: ChEMBL (422467)
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
BioActive Compounds: 4
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.

Putative Target:

ChEMBL Target ID: 90
Target Type: SINGLE PROTEIN
Pref Name: Dopamine D4 receptor
Synonyms: D(2C) dopamine receptor;D(4) dopamine receptor;Dopamine D4 receptor;
Gene Name: DRD4;
Protein Accession: P21917;
Protein GI: 1345939;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: membrane receptor 7tm1 smallmol monoamine receptor dopamine receptor
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment
Assay Type: Functional

Assay Data Source: Scientific Literature

BAO: Assay Format: cell-based format

Assay Cell Type: HEK293

Result Definitions
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

* Activity Concentration.

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