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

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.

BioChemical Class

GPCR secretin

UniProt ID

CRFR1_HUMAN

Sequence

MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPA
GQLVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAV
IINYLGHCISLVALLVAFVLFLRLRPGCTHWGDQADGALEVGAPWSGAPFQVRRSIRCLR
NIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVGWCRLVTAAYNYFHVTNFFWMFGEGC
YLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAIGKLYYDNEKCWFGKRPGVYTDYI
YQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKAVKATLVLLPLLGITYMLFF
VNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRKRWHRWQDKHSIRARV
ARAMSIPTSPTRVSFHSIKQSTAV

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 1 Approved Drugs

Telavancin

Drug Info

Approved

Staphylococcus infection

[2]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

Pexacerfont

Drug Info

Phase 2/3

Anxiety disorder

[3]

GSK561679

Drug Info

Phase 2

Major depressive disorder

[4]

ONO-2333Ms

Drug Info

Phase 2

Anxiety disorder

[5]

SSR125543

Drug Info

Phase 2

Anxiety disorder

[6]

GSK586529

Drug Info

Phase 1

Anxiety disorder

[7]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

CP-316,311

Drug Info

Discontinued in Phase 2

Mood disorder

[8]

GW876008

Drug Info

Discontinued in Phase 2

Irritable bowel syndrome

[9]

Antalarmin

Drug Info

Terminated

Depression

[12], [13]

DMP-696

Drug Info

Terminated

Anxiety disorder

[14], [15]

NBI-37582

Drug Info

Terminated

Depression

[16]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

CRA1000

Drug Info

Preclinical

Anxiety disorder

[10], [11]

Mode of Action

[+] 2 Modes of Action

Antagonist

[+] 14 Antagonist drugs

Telavancin

Drug Info

[1]

Pexacerfont

Drug Info

[9]

GSK561679

Drug Info

[17]

ONO-2333Ms

Drug Info

[18]

SSR125543

Drug Info

[19]

GSK586529

Drug Info

[17]

CP-316,311

Drug Info

[9]

GW876008

Drug Info

[9]

CRA1000

Drug Info

[1]

Antalarmin

Drug Info

[20]

NBI-37582

Drug Info

[22]

CP154,526

Drug Info

[1]

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

Drug Info

[1]

DMP-695/696

Drug Info

[1]

Inhibitor

[+] 7 Inhibitor drugs

DMP-696

Drug Info

[21]

BMS-561388

Drug Info

[23]

CP-376395

Drug Info

[24]

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

Drug Info

[25]

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

Drug Info

[25]

PD-171729

Drug Info

[26]

SR-125543A

Drug Info

[27]

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

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

Top

Target Validation

Target Validation Info

References

Top

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

REF 6

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 7

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

REF 8

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 9

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

REF 10

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 11

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 12

REF 13

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 14

REF 15

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 16

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

REF 17

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

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

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 21

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 22

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

REF 23

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 24

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

REF 25

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 26

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

REF 27

2-Arylpyrimidines: novel CRF-1 receptor antagonists. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4486-90.

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