Target Information

Target General Information

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Target ID

T57680 (Former ID: TTDR00186)

Target Name

Soluble guanylate cyclase (GCS)

Synonyms

GUCY1; GUCS; GUC1; GCS

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Gene Name

GUCY1A1; GUCY1B1

Target Type

Successful target

[1]

Disease

[+] 4 Target-related Diseases

Angina pectoris [ICD-11: BA40]

Diabetic foot ulcer [ICD-11: BD54]

Hypertension [ICD-11: BA00-BA04]

Respiratory failure [ICD-11: CB41]

Function

Probably plays a specific functional role in the rods and/or cones of photoreceptors. It may be the enzyme involved in the resynthesis of cGMP required for recovery of the dark state after phototransduction.

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BioChemical Class

Phosphorus-oxygen lyase

UniProt ID

GCYA1_HUMAN ; GCYB1_HUMAN

Sequence

MFCTKLKDLKITGECPFSLLAPGQVPNESSEEAAGSSESCKATVPICQDIPEKNIQESLP
QRKTSRSRVYLHTLAESICKLIFPEFERLNVALQRTLAKHKIKESRKSLEREDFEKTIAE
QAVAAGVPVEVIKESLGEEVFKICYEEDENILGVVGGTLKDFLNSFSTLLKQSSHCQEAG
KRGRLEDASILCLDKEDDFLHVYYFFPKRTTSLILPGIIKAAAHVLYETEVEVSLMPPCF
HNDCSEFVNQPYLLYSVHMKSTKPSLSPSKPQSSLVIPTSLFCKTFPFHFMFDKDMTILQ
FGNGIRRLMNRRDFQGKPNFEEYFEILTPKINQTFSGIMTMLNMQFVVRVRRWDNSVKKS
SRVMDLKGQMIYIVESSAILFLGSPCVDRLEDFTGRGLYLSDIPIHNALRDVVLIGEQAR
AQDGLKKRLGKLKATLEQAHQALEEEKKKTVDLLCSIFPCEVAQQLWQGQVVQAKKFSNV
TMLFSDIVGFTAICSQCSPLQVITMLNALYTRFDQQCGELDVYKVETIGDAYCVAGGLHK
ESDTHAVQIALMALKMMELSDEVMSPHGEPIKMRIGLHSGSVFAGVVGVKMPRYCLFGNN
VTLANKFESCSVPRKINVSPTTYRLLKDCPGFVFTPRSREELPPNFPSEIPGICHFLDAY
QQGTNSKPCFQKKDVEDGNANFLGKASGID

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Drugs and Modes of Action

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Approved Drug(s)

[+] 3 Approved Drugs

Nitric Oxide

Drug Info

Approved

Respiratory failure

[2], [3]

Nitroglycerin

Drug Info

Approved

Diabetic foot ulcer

[4]

Sodium nitroprusside

Drug Info

Approved

Hypertension

[5]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

CTI-1601

Drug Info

Phase 2

Friedreich's ataxia

[6]

CY6463

Drug Info

Phase 2

Alzheimer disease

[7]

IW-1973

Drug Info

Phase 2

Heart failure

[8]

MK-5475

Drug Info

Phase 2

Pulmonary arterial hypertension

[9]

Runcaciguat

Drug Info

Phase 2

Chronic kidney disease

[10]

Mode of Action

[+] 4 Modes of Action

Stimulator

[+] 4 Stimulator drugs

Nitric Oxide

Drug Info

[11]

CTI-1601

Drug Info

[12]

CY6463

Drug Info

[13]

MK-5475

Drug Info

[15]

Modulator

[+] 3 Modulator drugs

Nitroglycerin

Drug Info

[1], [5]

Sodium nitroprusside

Drug Info

[5]

CY6463

Drug Info

[14]

Agonist

[+] 1 Agonist drugs

IW-1973

Drug Info

[8]

Activator

[+] 2 Activator drugs

Runcaciguat

Drug Info

[16]

(5-(1-benzyl-1H-indazol-3-yl)furan-2-yl)methanol

Drug Info

[1]

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

References

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REF 1

Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction. Int J Impot Res. 2002 Feb;14(1):8-14.

REF 2

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: 2509).

REF 3

Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome. Expert Opin Emerg Drugs. 2007 Sep;12(3):461-77.

REF 4

Emerging drugs for diabetic foot ulcers. Expert Opin Emerg Drugs. 2006 Nov;11(4):709-24.

REF 5

Stimulators and activators of soluble guanylate cyclase: review and potential therapeutic indications.Crit Care Res Pract.2012;2012:290805.

REF 6

ClinicalTrials.gov (NCT05579691) A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose Exploration Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 in Adult Subjects With Friedreich's Ataxia. U.S.National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT04798989) A Phase 2a Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CY6463 When Administered to Participants With Alzheimer's Disease and Vascular Pathology. U.S.National Institutes of Health.

REF 8

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 9

ClinicalTrials.gov (NCT05612035) A Phase 2a Randomized, Placebo-Controlled Clinical Study to Evaluate the Efficacy and Safety of MK-5475 in Adults With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease. U.S.National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT04507061) A Randomized, Double-blind, Placebo-controlled, Multi-center Study to Assess the Safety and Efficacy of Individually Titrated Oral Doses of Runcaciguat in Subjects With Clinical Diagnosis of Chronic Kidney Disease With Diabetes and/or Hypertension and at Least One Cardiovascular Comorbidity. U.S.National Institutes of Health.

REF 11

Nitric oxide and nitrovasodilators: similarities, differences, and interactions. Am J Cardiol. 1996 May 30;77(13):2C-7C.

REF 12

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases. Front Pharmacol. 2021 May 24;12:656561.

REF 13

First-in-human trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator. Clin Transl Sci. 2023 Aug;16(8):1381-1395.

REF 14

Clinical pipeline report, company report or official report of Cyclerion Therapeutics

REF 15

Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Respir Med. 2023 Jan;206:107065.

REF 16

Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease. Naunyn Schmiedebergs Arch Pharmacol. 2021 Dec;394(12):2363-2379.

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