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BioAssay: AID 632806

Agonist activity at human GRLN receptor expressed in HEK293 cells assessed as calcium binding by Ca2+ bioluminescence aequorin assay

High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such more ..
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 Tested Compounds
 Tested Compounds
All(51)
 
 
Active(19)
 
 
Inconclusive(32)
 
 
 Tested Substances
 Tested Substances
All(51)
 
 
Active(19)
 
 
Inconclusive(32)
 
 
AID: 632806
Data Source: ChEMBL (790254)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2012-09-09
Modify Date: 2014-05-24

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Appetite-regulating hormone; AltName: Full=Growth hormone secretagogue; AltName: Full=Growth hormone-releasing peptide; AltName: Full=Motilin-related peptide; AltName: Full=Protein M46; Contains: RecName: Full=Ghrelin-27; Contains: RecName: Full=Ghrelin-28; Short=Ghrelin; Contains: RecName: Full=Obestatin; Flags: Precursor
Description ..   
Protein Family: Motilin/ghrelin-associated peptide
Comment ..   

Gene:GHRL     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 19
Description:
Title: Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic.

Abstract: High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' beta-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.
(PMID: 22106937)
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: Binding

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
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6EC50 activity commentEC50 activity commentString
7EC50 standard flagEC50 standard flagInteger
8EC50 qualifierEC50 qualifierString
9EC50 published valueEC50 published valueFloatnM
10EC50 standard valueEC50 standard valueFloatnM

* Activity Concentration.

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