A Study to Investigate the Efficacy and Tolerability of Two Dose Levels of Lerisetron Compared With Granisetron in Patients Receiving Radiotherapy for Stage I Seminoma

RATIONALE: Antiemetic drugs may help to reduce or prevent nausea and vomiting in patients treated with radiation therapy. It is not yet known whether lerisetron is more effective than granisetron in preventing nausea and vomiting.
PURPOSE: Randomized phase III trial to compare the effectiveness of lerisetron with that of granisetron in preventing nausea and vomiting in men who are being treated with radiation therapy for stage I seminoma.

Start Date-

Sponsor / Collaborator

Simbec Research Ltd.

100 Clinical Results associated with Lerisetron

100 Translational Medicine associated with Lerisetron

100 Patents (Medical) associated with Lerisetron

Literatures (Medical) associated with Lerisetron

31 Mar 2020·ACS Omega

Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure–Activity Relationship Studies, and Biological Assessment

Article

Author: Tanner, Lloyd ; Reddy, Virsinha ; Zou, Bin ; Mebrahtu, Fanuel ; Rottmann, Matthias ; Street, Leslie J. ; Kondreddi, Ravinder R. ; Chibale, Kelly ; Mueller, Rudolf ; Lawrence, Nina ; Nchinda, Aloysius T. ; Barnabe, Marine ; Taylor, Dale ; Lakshminarayana, Suresh B. ; Eyermann, Charles J.

A phenotypic whole cell high-throughput screen against the asexual blood and liver stages of the malaria parasite identified a benzimidazole chemical series. Among the hits were the antiemetic benzimidazole drug Lerisetron 1 (IC₅₀ NF54 = 0.81 μM) and its methyl-substituted analogue 2 (IC₅₀ NF54 = 0.098 μM). A medicinal chemistry hit to lead effort led to the identification of chloro-substituted analogue 3 with high potency against the drug-sensitive NF54 (IC₅₀ NF54 = 0.062 μM) and multidrug-resistant K1 (IC₅₀ K1 = 0.054 μM) strains of the human malaria parasite Plasmodium falciparum. Compounds 2 and 3 gratifyingly showed in vivo efficacy in both Plasmodium berghei and P. falciparum mouse models of malaria. Cardiotoxicity risk as expressed in strong inhibition of the human ether-a-go-go-related gene (hERG) potassium channel was identified as a major liability to address. This led to the synthesis and biological assessment of around 60 analogues from which several compounds with improved antiplasmodial potency, relative to the lead compound 3, were identified.

01 Nov 2005·Pharmaceutical ResearchQ3 · MEDICINE

Pharmacokinetic–Pharmacodynamic Modeling of the Hydroxy Lerisetron Metabolite L6-OH in Rats: An Integrated Parent–Metabolite Model

Q3 · MEDICINE

Article

Author: Nerea Jauregizar ; Leire de la Fuente ; Fátima Ortega ; John C. Lukas ; Elena Suárez ; Rosario Calvo ; Ana Gonzalo ; Antonio Quintana ; Maria Luisa Lucero ; Aurelio Orjales

PURPOSEThe twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect.METHODSThe PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 microg kg(-1), i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent-metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry.RESULTSL6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC(50) = 0.098 ng mL(-1) and EC(50unbound) = 0.040 ng mL(-1)). Total clearance for L (PK-2) in the presence of generated L6-OH (CL(L) = CL(-->L6-OH) + CL(n)) was 0.0139 L min(-1). Most of this clearance was L6-OH formation (F(c) = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp(L6)) generated after a lerisetron therapeutic dose (10 microg kg(-1)) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp(L6max) was less than the EC(50) of L6-OH.CONCLUSIONSWe conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.

01 Oct 2004·Journal of Computer-Aided Molecular DesignQ3 · BIOLOGY

Subunit rotation models activation of serotonin 5-HT3AB receptors by agonists

Q3 · BIOLOGY

Article

Author: Zsolt Bikádi ; Miklós Simonyi ; Gábor Maksay

The N-terminal extracellular regions of heterooligomeric 3AB-type human 5-hydroxytryptamine receptors (5-HT3ABR) were modelled based on the crystal structure of snail acetylcholine binding protein AChBP. Stepwise rotation of subunit A by 5 degrees was performed between -10 degrees and 15 degrees to mimic agonist binding and receptor activation. Anticlockwise rotation reduced the size of the binding cavity in interface AB and reorganised the network of hydrogen bonds along the interface. AB subunit dimers with different rotations were applied for docking of ligands with different efficacies: 5-HT, m-chlorophenylbiguanide, SR 57227, quinolinyl piperazine and lerisetron derivatives. All ligands were docked into the dimer with -10 degrees rotation representing ligand-free, open binding cavities similarly, without pharmacological discrimination. Their ammonium ions were in hydrogen bonding distance to the backbone carbonyl of W183. Anticlockwise rotation and contraction of the binding cavity led to distinctive docking interactions of agonists with E129 and cation-pi interactions of their ammonium ions. Side chains of several further amino acids participating in docking (Y143, Y153, Y234 and E236) are in agreement with the effects of point mutations in the binding loops. Our model postulates that 5-HT binds to W183 in a hydrophobic cleft as well as to E236 in a hydrophilic vestibule. Then it elicits anticlockwise rotation to draw in loop C via pi-cation-pi interactions of its ammonium ion with W183 and Y234. Finally, closure of the binding cavity might end in rebinding of 5-HT to E129 in the hydrophilic vestibule.

100 Deals associated with Lerisetron

External Link

KEGG	Wiki	ATC	Drug Bank
-	Lerisetron	-	DB12964

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Seminoma	Phase 3	-	Simbec Research Ltd.	09 Aug 2004
Testicular Germ Cell Tumor	Phase 3	-	Simbec Research Ltd.	09 Aug 2004
Vomiting	Phase 3	-	Simbec Research Ltd.	09 Aug 2004
Nausea	Phase 3	-	Faes Farma SA	-
Nausea	Phase 3	-	Faes Farma SA	-
Nausea and vomiting	Phase 3	ES	Faes Farma SA	-
Nausea and vomiting	Phase 3	ES	Faes Farma SA	-

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