Delving into the Latest Updates on Cicletanine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Cicletanine (USAN/INN), cycletanide

+ [5]

Target

α-adrenergic receptor x β-adrenoceptors

Action

agonists

Mechanism

α-adrenergic receptor agonists(Alpha adrenergic receptor agonists), β-adrenoceptors agonists(Beta adrenergic receptors agonists)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Hypertension

Inactive Indication

Diabetes MellitusHypokalemiaHyponatremia+ [1]

Originator Organization

Ipsen SA

Active Organization

Ipsen SA

Inactive Organization

Gilead Sciences, Inc.Navitas Pharma, Inc.

License Organization-

Drug Highest PhaseApproved

First Approval Date

Japan (01 Jan 1988),

Hypertension

RegulationOrphan Drug (United States)

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Structure/Sequence

Molecular FormulaC14H12ClNO2

InChIKeyCVKNDPRBJVBDSS-UHFFFAOYSA-N

CAS Registry89943-82-8

View All Structures (2)

Cicletanine, which has been approved and launched for hypertension in France and Germany, has promise beyond hypertension in critically-unmet needs such as diabetes. It is evident from in vitro, animal and human studies that cicletanine's optimal dose in diabetes and other challenging, critically-unmet needs is likely to be higher than that for hypertension. Cicletanine's maximum tolerated dosage is not known, but the drug's dose-limiting effects are documented to be potassium loss and sodium loss from thiazide-type activity (one of the therapeutic mechanisms the drug is known to have); such thiazide-type losses are known to be reversed safely by magnesium. This trial explores the ability of magnesium to enhance cicletanine safety at higher doses in a trial involving patients with hypertension complicated by diabetes.

Start Date01 Jun 2022

Sponsor / Collaborator

Navitas Pharma, Inc.

[+1]

NCT00832507

/ TerminatedPhase 2

A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-ranging Study of Cicletanine in Subjects With Pulmonary Arterial Hypertension

This Phase 2, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study will compare the efficacy, safety, and tolerability of cicletanine hydrochloride (HCl) to placebo in subjects with PAH. Study drug will be administered alone, or on the background of stable PAH therapy. The study will consist of 3 periods: a screening period, a 12-week placebo-controlled treatment period, and a long-term, blinded extension period.

Start Date01 Jan 2009

Sponsor / Collaborator

Gilead Sciences, Inc.

100 Clinical Results associated with Cicletanine

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100 Translational Medicine associated with Cicletanine

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100 Patents (Medical) associated with Cicletanine

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279

Literatures (Medical) associated with Cicletanine

13 Jun 2024·Journal of Medicinal Chemistry

Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability

Article

Author: Rodde, Stephane ; Strang, Ross ; Dittrich, Birger ; Möbitz, Henrik

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pK_a is significantly lower than the basic pK_a. Through concordance of measured and calculated pK_a and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpK_a. These nonclassical zwitterions are characterized by a weak acidic and basic pK_a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

01 Sep 2016·Kidney Research and Clinical PracticeQ3 · MEDICINE

Cicletanine-induced hyponatremia and hypokalemia in kidney transplant patients

Q3 · MEDICINE

ArticleOA

Author: Choi, Eun Young ; Choi, Jong-Wook ; Kang, Chong Myung ; Ro, Youngouk ; Kim, Gheun-Ho

BACKGROUNDCicletanine is an antihypertensive agent with vasorelaxant and diuretic properties. It has been widely used in European countries; however, cicletanine-associated electrolyte disturbances have yet to be defined. We investigated cicletanine-induced hyponatremia and hypokalemia in kidney transplant patients.METHODSData from a total of 68 kidney transplant recipients who were treated for hypertension with cicletanine were retrospectively analyzed. Cicletanine-induced hyponatremia and hypokalemia were defined as serum sodium < 135 mmol/L and potassium < 3.5 mmol/L, respectively, after the use of cicletanine.RESULTSThe average patient age was 50 (±11) years, and 44 (65%) were male. The daily dose of cicletanine was 171 ± 46 mg, and the duration of drug use was 215 ± 514 days. Hyponatremia occurred in 11 patients (16.2%), and hypokalemia occurred in 8 patients (11.8%). Three patients (4.4%) had hyponatremia and hypokalemia simultaneously. The duration of cicletanine administration was significantly longer in patients with hyponatremia than in those without hyponatremia (943 ± 958 vs. 74 ± 166 days, P < 0.05). The occurrence of hypokalemia was not affected by either daily dose or duration of drug use. Among 11 patients with hyponatremia, 10 were corrected within 2 weeks after withdrawal of the drug and 1 was spontaneously corrected. Among 8 cases of hypokalemia, 7 were corrected after withdrawal of the drug and 1 was spontaneously corrected.CONCLUSIONWe demonstrate that cicletanine may induce hyponatremia or hypokalemia in kidney transplant patients. Hyponatremia is more frequently associated with cicletanine than hypokalemia, and extended use of cicletanine may increase the risk of hyponatremia.

15 Jul 2013·American Journal of Physiology-Gastrointestinal and Liver PhysiologyQ3 · MEDICINE

Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells

Q3 · MEDICINE

Article

Author: Liu, Songling ; Rockey, Don C.

The function of the endothelial isoform of nitric oxide synthase (eNOS) and production of nitric oxide (NO) is altered in a number of disease states. Pharmacological approaches to enhancing NO synthesis and thus perhaps endothelial function could have substantial benefits in patients. We analyzed the effect of cicletanine, a synthetic pyridine with potent vasodilatory characteristics, on eNOS function and NO production in normal (liver) and injured rat sinusoidal endothelial cells, and we studied the effect of cicletanine-induced NO on stellate cell contraction and portal pressure in an in vivo model of liver injury. Sinusoidal endothelial cells were isolated from normal and injured rat livers. After exposure to cicletanine, eNOS phosphorylation, NO synthesis, and the signaling pathway regulating eNOS activation were measured. Cicletanine led to an increase in eNOS (Ser1177) phosphorylation, cytochrome c reductase activity, l-arginine conversion to l-citrulline, as well as NO production. The mechanism of the effect of cicletanine appeared to be via the protein kinase B (Akt) and MAP kinase/Erk signaling pathways. Additionally, cicletanine improved NO synthesis in injured sinusoidal endothelial cells. NO production induced by cicletanine in sinusoidal endothelial cells increased protein kinase G (PKG) activity as well as relaxation of stellate cells. Finally, administration of cicletanine to mice with portal hypertension induced by bile duct ligation led to reduction of portal pressure. The data indicate that cicletanine might improve eNOS activity in injured sinusoidal endothelial cells and likely activates hepatic stellate cell NO/PKG signaling. It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients.

100 Deals associated with Cicletanine

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External Link

KEGG	Wiki	ATC	Drug Bank
D03487	Cicletanine	C03BX03	DB12766

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hypertension	Japan	Ipsen SA	01 Jan 1988

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Phase 2	Mexico	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Germany	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Israel	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Australia	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Belgium	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Canada	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	United Kingdom	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	United States	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Spain	Gilead Sciences, Inc.	01 Jan 2009
Pulmonary Arterial Hypertension	Phase 2	Austria	Gilead Sciences, Inc.	01 Jan 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ERS2012	Phase 2	Pulmonary Arterial Hypertension	162	Cicletanine 150 mg qd	(hsmxogwnov) = lsxcgplhtv qkcnqrqsjt (anfmuxiauy, -8.0 to 24.0)	Negative	01 Sep 2012
ERS2012	Phase 2	Pulmonary Arterial Hypertension	162	Cicletanine 150 mg bid	(hsmxogwnov) = fgeowhzsck qkcnqrqsjt (anfmuxiauy, -8.0 to 24.0)	Negative	01 Sep 2012
FP321 (ERA2012)	Not Applicable	Hypokalemia \| Hyponatremia	68	Cicletanine	djwhtnpceu(xirxivkflf) = Cicletanine-induced hypokalemia occurred in 8 (11.8%) dcvuabwzia (apfjalfojp ) View more	Positive	01 May 2012