Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Sodium/hydrogen exchanger 1 (SLC9A1)
• Synonyms: Solute carrier family 9 member 1; Na+/H+ antiporter, amiloride-sensitive; Na(+)Sodium/hydrogen exchanger 1/H(+) exchanger 1; Na(+)/H(+) exchanger 1; Na(+)/H(+) antiporter, amiloride-sensitive; NHE1; NHE-1; Myocardial Na+/H+ exchanger; APNH1; APNH
• Gene Name: SLC9A1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Monovalent cation:proton antiporter-1
• UniProt ID: SL9A1_HUMAN
• TTD ID: T82028
• Sequence:
  MVLRSGICGLSPHRIFPSLLVVVALVGLLPVLRSHGLQLSPTASTIRSSEPPRERSIGDV
  TTAPPEVTPESRPVNHSVTDHGMKPRKAFPVLGIDYTHVRTPFEISLWILLACLMKIGFH
  VIPTISSIVPESCLLIVVGLLVGGLIKGVGETPPFLQSDVFFLFLLPPIILDAGYFLPLR
  QFTENLGTILIFAVVGTLWNAFFLGGLMYAVCLVGGEQINNIGLLDNLLFGSIISAVDPV
  AVLAVFEEIHINELLHILVFGESLLNDAVTVVLYHLFEEFANYEHVGIVDIFLGFLSFFV
  VALGGVLVGVVYGVIAAFTSRFTSHIRVIEPLFVFLYSYMAYLSAELFHLSGIMALIASG
  VVMRPYVEANISHKSHTTIKYFLKMWSSVSETLIFIFLGVSTVAGSHHWNWTFVISTLLF
  CLIARVLGVLGLTWFINKFRIVKLTPKDQFIIAYGGLRGAIAFSLGYLLDKKHFPMCDLF
  LTAIITVIFFTVFVQGMTIRPLVDLLAVKKKQETKRSINEEIHTQFLDHLLTGIEDICGH
  YGHHHWKDKLNRFNKKYVKKCLIAGERSKEPQLIAFYHKMEMKQAIELVESGGMGKIPSA
  VSTVSMQNIHPKSLPSERILPALSKDKEEEIRKILRNNLQKTRQRLRSYNRHTLVADPYE
  EAWNQMLLRRQKARQLEQKINNYLTVPAHKLDSPTMSRARIGSDPLAYEPKEDLPVITID
  PASPQSPESVDLVNEELKGKVLGLSRDPAKVAEEDEDDDGGIMMRSKETSSPGTDDVFTP
  APSDSPSSQRIQRCLSDPGPHPEPGEGEPFFPKGQ
• Function: Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions.
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Regulation of actin cytoskeleton (hsa04810)
  Thyroid hormone signaling pathway (hsa04919)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway: Hyaluronan uptake and degradation (R-HSA-2160916)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zoniporide hydrochloride	DM8L7JD	Angina pectoris	BA40	Phase 3	[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	[2]
ENIPORIDE	DME7OCX	Cardiac arrhythmias	BC9Z	Discontinued in Phase 2	[3]
HOE-694	DML0B97	Heart arrhythmia	BC65	Terminated	[4]

16 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5'-(N-ethyl-N-isopropyl)amiloride	DM3TPMO	Discovery agent	N.A.	Investigative	[5]
BIIB-513	DML4DQ3	Myocardial infarction	BA41-BA43	Investigative	[6]
Homoserine Lactone	DMTKN4A	Discovery agent	N.A.	Investigative	[7]
N-(3-Methanesulfonyl-4-methoxy-benzoyl)-guanidine	DM0H8CK	Discovery agent	N.A.	Investigative	[4]
N-(3-Methanesulfonyl-4-methyl-benzoyl)-guanidine	DMSVQJP	Discovery agent	N.A.	Investigative	[4]
N-(4-Bromo-3-methanesulfonyl-benzoyl)-guanidine	DMC28SN	Discovery agent	N.A.	Investigative	[4]
N-(4-Chloro-3-methanesulfonyl-benzoyl)-guanidine	DMFG6MU	Discovery agent	N.A.	Investigative	[4]
N-(4-Cyano-3-methanesulfonyl-benzoyl)-guanidine	DMGI9EA	Discovery agent	N.A.	Investigative	[4]
N-(5-m-Tolyl-furan-2-carbonyl)-guanidine	DMS2X69	Discovery agent	N.A.	Investigative	[8]
N-(5-Methanesulfonyl-2-methyl-benzoyl)-guanidine	DM91463	Discovery agent	N.A.	Investigative	[4]
N-(5-o-Tolyl-furan-2-carbonyl)-guanidine	DMFNZSL	Discovery agent	N.A.	Investigative	[8]
N-(5-Phenyl-furan-2-carbonyl)-guanidine	DMNU68D	Discovery agent	N.A.	Investigative	[8]
N-[2-(1H-benzoimidazol-2-yl)-benzoyl]-guanidine	DMI9GQV	Discovery agent	N.A.	Investigative	[9]
N-[4-(1H-benzoimidazol-2-yl)-benzoyl]-guanidine	DMT6LX9	Discovery agent	N.A.	Investigative	[9]
N-[5-(2-Ethyl-phenyl)-furan-2-carbonyl]-guanidine	DMP5A8K	Discovery agent	N.A.	Investigative	[8]
N-[5-(2-Nitro-phenyl)-furan-2-carbonyl]-guanidine	DMZ9V18	Discovery agent	N.A.	Investigative	[8]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Sodium/hydrogen exchanger 1 (SLC9A1) DTP Info
• Gene Name: SLC9A1

References

• [1] Zoniporde: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1). Cardiovasc Drug Rev. 2003 Spring;21(1):17-32.
• [2] Synthesis and bioactivity of substituted indan-1-ylideneaminoguanidine derivatives. Eur J Med Chem. 2009 Sep;44(9):3771-6.
• [3] Bicyclic acylguanidine Na+/H+ antiporter inhibitors. J Med Chem. 1998 Sep 10;41(19):3736-47.
• [4] (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. J Med Chem. 1997 Jun 20;40(13):2017-34.
• [5] NHE1 inhibition by amiloride- and benzoylguanidine-type compounds. Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous ... J Biol Chem. 2007 Jul 6;282(27):19716-27.
• [6] 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. (Target id: 948).
• [7] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [8] (5-Arylfuran-2-ylcarbonyl)guanidines as cardioprotectives through the inhibition of Na+/H+ exchanger isoform-1. J Med Chem. 2005 Apr 21;48(8):2882-91.
• [9] Benzimidazol-2-yl or benzimidazol-2-ylthiomethyl benzoylguanidines as novel Na+/H+ exchanger inhibitors, synthesis and protection against ischemic-... Bioorg Med Chem Lett. 2007 May 1;17(9):2430-3.