Target Information

Target General Information

Target ID

T45262 (Former ID: TTDC00073)

Target Name

Corticotropin-releasing factor receptor 1 (CRHR1)

Synonyms

Corticotropin-releasing hormone type 1 receptor; Corticotropin-releasing hormone receptor 1; CRHR1; CRH-R 1; CRF1; CRF-R1; CRF-R; CRF-1 receptor; CRF receptor

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Gene Name

CRHR1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Staphylococcal/streptococcal disease [ICD-11: 1B5Y]

Function

G-protein coupled receptor for CRH (corticotropin- releasing factor) and UCN (urocortin). Has high affinity for CRH and UCN. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and down-stream effectors, such as adenylate cyclase. Promotes the activation of adenylate cyclase, leading to increased intracellular cAMP levels. Inhibits the activity of the calcium channel CACNA1H. Required for normal embryonic development of the adrenal gland and for normal hormonal responses to stress. Plays a role in the response to anxiogenic stimuli.

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BioChemical Class

GPCR secretin

UniProt ID

CRFR1_HUMAN

Sequence

MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPA
GQLVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAV
IINYLGHCISLVALLVAFVLFLRLRPGCTHWGDQADGALEVGAPWSGAPFQVRRSIRCLR
NIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVGWCRLVTAAYNYFHVTNFFWMFGEGC
YLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAIGKLYYDNEKCWFGKRPGVYTDYI
YQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKAVKATLVLLPLLGITYMLFF
VNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRKRWHRWQDKHSIRARV
ARAMSIPTSPTRVSFHSIKQSTAV

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3D Structure

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PDB

HIT2.0 ID

T85RZS

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Telavancin

Drug Info

Approved

Staphylococcus infection

[2]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

ONO-2333Ms

Drug Info

Phase 2

Anxiety disorder

[6]

SSR125543

Drug Info

Phase 2

Anxiety disorder

[7]

GSK586529

Drug Info

Phase 1

Anxiety disorder

[8]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

CP-316,311

Drug Info

Discontinued in Phase 2

Mood disorder

[9]

GW876008

Drug Info

Discontinued in Phase 2

Irritable bowel syndrome

[10]

Antalarmin

Drug Info

Terminated

Depression

[13], [14]

DMP-696

Drug Info

Terminated

Anxiety disorder

[15], [16]

NBI-37582

Drug Info

Terminated

Depression

[17]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

CRA1000

Drug Info

Preclinical

Anxiety disorder

[11], [12]

Mode of Action

[+] 2 Modes of Action

Antagonist

[+] 12 Antagonist drugs

Telavancin

Drug Info

[1]

ONO-2333Ms

Drug Info

[18]

SSR125543

Drug Info

[19]

GSK586529

Drug Info

[20]

CP-316,311

Drug Info

[10]

GW876008

Drug Info

[10]

CRA1000

Drug Info

[1]

Antalarmin

Drug Info

[21]

NBI-37582

Drug Info

[23]

CP154,526

Drug Info

[1]

Des-Arg(9)-[Leu(8)]-BK

Drug Info

[1]

DMP-695/696

Drug Info

[1]

Inhibitor

[+] 6 Inhibitor drugs

DMP-696

Drug Info

[22]

BMS-561388

Drug Info

[24]

CP-376395

Drug Info

[25]

N-mesityl-4,6-dimethyl-3-tosylpyridin-2-amine

Drug Info

[26]

N-mesityl-6-methyl-3-tosylpyridin-2-amine

Drug Info

[26]

PD-171729

Drug Info

[27]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Long-term depression	hsa04730	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	8.31E-04
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	4.00E-01
Neighborhood connectivity	1.60E+01	Topological coefficient	2.09E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Long-term depression

NetPath Pathway

[+] 1 NetPath Pathways

TNFalpha Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Cortocotropin releasing factor receptor signaling pathway

Reactome

[+] 2 Reactome Pathways

Class B/2 (Secretin family receptors)

G alpha (s) signalling events

WikiPathways

[+] 5 WikiPathways

GPCRs, Class B Secretin-like

Myometrial Relaxation and Contraction Pathways

Corticotropin-releasing hormone

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

A review of drug options in age-related macular degeneration therapy and potential new agents. Expert Opin Pharmacother. 2006 Dec;7(17):2355-68.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

ClinicalTrials.gov (NCT00481325) Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder. U.S. National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT01187511) Effects of Corticotropin-Releasing Hormone Receptor 1 (CRH1) Antagonism on Stress-Induced Craving in Alcoholic Women With High Anxiety. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT05370521) A Randomized, Placebo-Controlled, Dose Escalation Study to Evaluate the Safety and Efficacy of Tildacerfont in Adult Subjects With Polycystic Ovary Syndrome (PCOS) and Elevated Adrenal Androgens. U.S.National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT00514865) Placebo-Controlled Study of ONO-2333Ms in Patients With Recurrent Major Depressive Disorder. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT01034995) A Trial Evaluating the Efficacy and Tolerability of SSR125543 in Outpatients With Major Depressive Disorder. U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT00703547) A First Time in Human Study of GSK586529 in Healthy Volunteers. U.S. National Institutes of Health.

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009248)

REF 10

Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.

REF 11

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3498).

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010650)

REF 13

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007484)

REF 15

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011782)

REF 17

Strategies for producing faster acting antidepressants. Drug Discov Today. 2005 Apr 15;10(8):578-85.

REF 18

Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend. 2013 Mar 1;128(3):175-86.

REF 19

Pharma & Vaccines. Product Development Pipeline. April 29 2009.

REF 20

Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).

REF 21

Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress. Life Sci. 1999;65(4):PL53-8.

REF 22

In vitro intrinsic clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists. J Med Chem. 2009 Jul 23;52(14):4161-72.

REF 23

CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.

REF 24

8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists. J Med Chem. 2009 May 14;52(9):3073-83.

REF 25

2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. J Med Chem. 2008 Mar 13;51(5):1385-92.

REF 26

Synthesis and evaluation of 2-anilino-3-phenylsulfonyl-6-methylpyridines as corticotropin-releasing factor1 receptor ligands. Bioorg Med Chem Lett. 2006 Feb 15;16(4):934-7.

REF 27

Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists. Bioorg Med Chem Lett. 1998 Aug 18;8(16):2067-70.

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