Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Sodium/hydrogen exchanger 3 (SLC9A3)
• Synonyms: SLC9A3; Na(+)/H(+) exchanger 3; NHE-3
• Gene Name: SLC9A3
• DTT Type: Successful target; [1]
• BioChemical Class: Monovalent cation:proton antiporter
• UniProt ID: SL9A3_HUMAN
• TTD ID: T92403
• Sequence:
  MWGLGARGPDRGLLLALALGGLARAGGVEVEPGGAHGESGGFQVVTFEWAHVQDPYVIAL
  WILVASLAKIGFHLSHKVTSVVPESALLIVLGLVLGGIVWAADHIASFTLTPTVFFFYLL
  PPIVLDAGYFMPNRLFFGNLGTILLYAVVGTVWNAATTGLSLYGVFLSGLMGDLQIGLLD
  FLLFGSLMAAVDPVAVLAVFEEVHVNEVLFIIVFGESLLNDAVTVVLYNVFESFVALGGD
  NVTGVDCVKGIVSFFVVSLGGTLVGVVFAFLLSLVTRFTKHVRIIEPGFVFIISYLSYLT
  SEMLSLSAILAITFCGICCQKYVKANISEQSATTVRYTMKMLASSAETIIFMFLGISAVN
  PFIWTWNTAFVLLTLVFISVYRAIGVVLQTWLLNRYRMVQLEPIDQVVLSYGGLRGAVAF
  ALVVLLDGDKVKEKNLFVSTTIIVVFFTVIFQGLTIKPLVQWLKVKRSEHREPRLNEKLH
  GRAFDHILSAIEDISGQIGHNYLRDKWSHFDRKFLSRVLMRRSAQKSRDRILNVFHELNL
  KDAISYVAEGERRGSLAFIRSPSTDNVVNVDFTPRSSTVEASVSYLLRENVSAVCLDMQS
  LEQRRRSIRDAEDMVTHHTLQQYLYKPRQEYKHLYSRHELTPTEDEKQDREIFHRTMRKR
  LESFKSTKLGLNQNKKAAKLYKRERAQKRRNSSIPNGKLPMESPAQNFTIKEKDLELSDT
  EEPPNYDEEMSGGIEFLASVTKDTASDSPAGIDNPVFSPDEALDRSLLARLPPWLSPGET
  VVPSQRARTQIPYSPGTFCRLMPFRLSSKSVDSFLQADGPEERPPAALPESTHM
• Function: Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.
• KEGG Pathway:
  Proximal tubule bicarbonate reclamation (hsa04964)
  Protein digestion and absorption (hsa04974)
  Bile secretion (hsa04976)
  Mineral absorption (hsa04978)
• Reactome Pathway: Sodium/Proton exchangers (R-HSA-425986)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tenapanor	DMCOZJY	Irritable bowel syndrome	DD91.0	Approved	[2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AVE-0657	DMESMHU	Cheyne-stokes respiration	MD11.Y	Phase 2	[3]
AZD1772//RDX5791	DMX5SG7	Chronic kidney disease	GB61	Phase 2	[1]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CARIPORIDE	DMV2DY3	Angina pectoris	BA40	Discontinued in Phase 2	[4]
ENIPORIDE	DME7OCX	Cardiac arrhythmias	BC9Z	Discontinued in Phase 2	[4]
HOE-694	DML0B97	Heart arrhythmia	BC65	Terminated	[5]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
N-(3-Methanesulfonyl-4-methoxy-benzoyl)-guanidine	DM0H8CK	Discovery agent	N.A.	Investigative	[5]
N-(3-Methanesulfonyl-4-methyl-benzoyl)-guanidine	DMSVQJP	Discovery agent	N.A.	Investigative	[5]
N-(4-Bromo-3-methanesulfonyl-benzoyl)-guanidine	DMC28SN	Discovery agent	N.A.	Investigative	[5]
N-(4-Chloro-3-methanesulfonyl-benzoyl)-guanidine	DMFG6MU	Discovery agent	N.A.	Investigative	[5]
N-(4-Cyano-3-methanesulfonyl-benzoyl)-guanidine	DMGI9EA	Discovery agent	N.A.	Investigative	[5]
N-(5-Methanesulfonyl-2-methyl-benzoyl)-guanidine	DM91463	Discovery agent	N.A.	Investigative	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Irritable bowel syndrome	DD91.0	Rectal colon tissue	6.83E-01	-0.03	-0.13

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Sodium/hydrogen exchanger 3 (SLC9A3) DTP Info
• Gene Name: SLC9A3

References

• [1] RDX5791, a First-in-Class Minimally Systemic NHE3 Inhibitor in Clinical Development for CIC and IBS-C, Increases Intestinal Sodium Leading to Enhanced Intestinal Fluid Volume and Transit. Gastroenterology. 2011;140(suppl 1):S99.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [3] Inhibition of central Na(+)/H(+) exchanger type 3 can alleviate sleep apnea in Sprague-Dawley rats. Chin Med J (Engl). 2014;127(1):48-53.
• [4] Bicyclic acylguanidine Na+/H+ antiporter inhibitors. J Med Chem. 1998 Sep 10;41(19):3736-47.
• [5] (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem. 1997 Jun 20;40(13):2017-34.