Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7EFHR)

• DTT 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
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR secretin
• UniProt ID: CRFR1_HUMAN
• TTD ID: T45262
• Sequence:
  MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPA
  GQLVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAV
  IINYLGHCISLVALLVAFVLFLRLRPGCTHWGDQADGALEVGAPWSGAPFQVRRSIRCLR
  NIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVGWCRLVTAAYNYFHVTNFFWMFGEGC
  YLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAIGKLYYDNEKCWFGKRPGVYTDYI
  YQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKAVKATLVLLPLLGITYMLFF
  VNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRKRWHRWQDKHSIRARV
  ARAMSIPTSPTRVSFHSIKQSTAV
• 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.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Long-term depression (hsa04730)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Telavancin	DM58VQX	Staphylococcus infection	1B5Y	Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pexacerfont	DMBJ15R	Anxiety disorder	6B00-6B0Z	Phase 2/3	[2]
GSK561679	DMEVARK	Alcohol dependence	6C40.2	Phase 2	[3]
ONO-2333Ms	DMOT0WR	Anxiety disorder	6B00-6B0Z	Phase 2	[4]
SSR125543	DMGJEB8	Anxiety disorder	6B00-6B0Z	Phase 2	[5]
Tildacerfont	DMAB8LH	Congenital adrenal hyperplasia	5A71.01	Phase 2	[6]
GSK586529	DM5E9LX	Anxiety disorder	6B00-6B0Z	Phase 1	[3]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CP-316,311	DMZ76EM	Major depressive disorder	6A70.3	Discontinued in Phase 2	[2]
GW876008	DMAXRBI	Irritable bowel syndrome	DD91.0	Discontinued in Phase 2	[2]
Antalarmin	DM2EKX5	Depression	6A70-6A7Z	Terminated	[7]
DMP-696	DMNSDM1	Anxiety disorder	6B00-6B0Z	Terminated	[8]
NBI-37582	DM3JY2N	Anxiety disorder	6B00-6B0Z	Terminated	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CRA1000	DMWMBIV	Anxiety disorder	6B00-6B0Z	Preclinical	[1]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-561388	DM3WBKN	Anxiety disorder	6B00-6B0Z	Investigative	[10]
CP-376395	DM93CA4	Discovery agent	N.A.	Investigative	[11]
CP154,526	DMYHR74	Depression	6A70-6A7Z	Investigative	[1]
Des-Arg(9)-[Leu(8)]-BK	DMVX9I0	Depression	6A70-6A7Z	Investigative	[1]
DMP-695/696	DMNRLA7	Depression	6A70-6A7Z	Investigative	[1]
N-mesityl-4,6-dimethyl-3-tosylpyridin-2-amine	DMI065U	Discovery agent	N.A.	Investigative	[12]
N-mesityl-6-methyl-3-tosylpyridin-2-amine	DMEUI8C	Discovery agent	N.A.	Investigative	[12]
PD-171729	DMJ3DOI	Discovery agent	N.A.	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	7.70E-01	-0.02	-0.1
Irritable bowel syndrome	DD91.0	Rectal colon tissue	8.26E-01	0.04	0.15

References

• [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.
• [2] Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.
• [3] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [4] Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend. 2013 Mar 1;128(3):175-86.
• [5] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [6] Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2021 Nov 30;186(1):R1-R14.
• [7] 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.
• [8] 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.
• [9] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
• [10] 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.
• [11] 2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. J Med Chem. 2008 Mar 13;51(5):1385-92.
• [12] 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.
• [13] Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists. Bioorg Med Chem Lett. 1998 Aug 18;8(16):2067-70.