Delving into the Latest Updates on CPL-500036 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [4]

Target

PDE10A

Mechanism

PDE10A inhibitors(Phosphodiesterase 10A inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseOther Diseases

Active Indication

Dyskinesia, Drug-InducedParkinson DiseaseSchizophrenia

Inactive Indication-

Originator Organization

Celon Pharma SA

Active Organization

Celon Pharma SA

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Phosphodiesterase 10A (PDE10A), the enzyme which catalyzes hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is located almost exclusively in striatal γ-amino-butyric acid (GABA)ergic medium spiny neurons (MSNs). Since dopaminergic deficiency in Parkinson's disease (PD) leads to functional imbalance of striatal direct and indirect output pathways formed by MSNs, PDE10A seems to be of special interest as a potential therapeutic target in PD. The aim of the present study was to examine the influence of 7-{5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl}-2-phenylimidazo[1,2-a]pyrimidine (CPL500036), a novel selective inhibitor of PDE10A, on sensorimotor deficits and therapeutic effects of L-3,4-dihydroxyphenylalanine (L-DOPA) in hemiparkinsonian rats. Animals were unilaterally lesioned with 6-hydroxydopamine, and their sensorimotor deficits were examined in the stepping, cylinder, vibrissae and catalepsy tests. CPL500036 (0.1 and 0.3 mg/kg) was administered either acutely or chronically (2 weeks), alone or in combination with L-DOPA/benserazide (6 mg/kg/6 mg/kg). Acute treatment with CPL500036 reversed the lesion-induced impairments of contralateral forelimb use in the stepping and cylinder tests but did not influence deficits in the vibrissae test and the lesion-induced catalepsy. Moreover, CPL500036 did not diminish the therapeutic effects produced by acute and chronic treatment with L-DOPA in these tests. The present study suggests a potential use of CPL500036 as a co-treatment to L-DOPA in PD therapy.

Frontiers in Pharmacology

A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects

Article

Author: Jakubowski, Piotr ; Dera, Paulina ; Bojarski, Lukasz ; Janicka, Monika ; Popik, Piotr ; Abramski, Krzysztof ; Welniak-Kaminska, Marlena ; Hołuj, Małgorzata ; Kos, Tomasz ; Pieczykolan, Jerzy ; Hucz-Kalitowska, Joanna ; Janowska, Sylwia ; Kokhanovska, Sofiya ; Rutkowska-Wlodarczyk, Izabela ; Matloka, Mikolaj ; Pankiewicz, Piotr ; Grieb, Paweł ; Wieczorek, Maciej ; Świątkiewicz, Maciej

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo.Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method.Results: CPL500036 inhibited PDE10A at an IC50 of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC50 of 9.2 µM. Despite inhibiting hERG tail current at an IC25 of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg.Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.

100 Deals associated with CPL-500036

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Dyskinesia, Drug-Induced	Phase 2	UA	Celon Pharma SA	02 Nov 2021
Dyskinesia, Drug-Induced	Phase 2	PL	Celon Pharma SA	02 Nov 2021
Parkinson Disease	Phase 2	PL	Celon Pharma SA	02 Nov 2021
Parkinson Disease	Phase 2	UA	Celon Pharma SA	02 Nov 2021
Schizophrenia	Phase 2	PL	Celon Pharma SA	19 May 2021
Schizophrenia	Phase 2	UA	Celon Pharma SA	19 May 2021
Schizophrenia	Phase 2	HU	Celon Pharma SA	19 May 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05278156 (Company_Website) Manual	Phase 2	Acute schizophrenia	189	CPL' 36 (20mg)	(lapfvggcwy) = jrzzwjwuxf vpckwkjmwr (mvoiznbues ) View more	Positive	05 Jul 2024
				CPL' 36 (40 mg)	(lapfvggcwy) = excpfhcojd vpckwkjmwr (mvoiznbues ) View more