Delving into the Latest Updates on Balipodect with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Balipodect (USAN/INN)

Target

PDE10A

Action

inhibitors

Mechanism

PDE10A inhibitors(Phosphodiesterase 10A inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Psychotic DisordersSchizophrenia

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Takeda Pharmaceutical Co., Ltd.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

RegulationOrphan Drug (European Union)

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Structure/Sequence

Molecular FormulaC23H17FN6O2

InChIKeyKVHRYLNQDWXAGI-UHFFFAOYSA-N

CAS Registry1238697-26-1

In briefThe cyclic adenosine monophosphate (cAMP) pathway is essential for maintaining sperm physiology. This study examines a cAMP analog and a phosphodiesterase inhibitor that effectively enhance human sperm motility, thereby improving the efficiency of in vitro sperm selection.AbstractcAMP plays a central role in sperm physiology. Various cAMP upregulators, both cAMP analogs and phosphodiesterase (PDE) inhibitors, have been used in handling human sperm in vitro, although conflicting results and variable responses among patients have been reported. This study aims to evaluate the ability of two compounds – Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3′-5′-cyclic monophosphothioate (cBiMPs), a cAMP analog, and TAK-063, a specific PDE10A inhibitor – to enhance human sperm motility parameters and, consequently, improve sperm preparation procedures. Our results showed that both cBiMPs and TAK-063 significantly enhanced human sperm motility and hyperactivation compared to the control (dimethyl sulphoxide). They also increased protein phosphorylation levels without inducing premature acrosomal exocytosis or DNA fragmentation. The enhancement of sperm motility persisted for 4 h after their removal, surpassing the effects of known cAMP analogs (8-bromo-adenosine-3′, 5′-cAMP (8-Br-cAMP) or dibutyryl cAMP (db-cAMP)) or PDE inhibitors (3-isobutyl-1-methylxanthine (IBMX) or pentoxifylline (PTX)). Furthermore, the presence of cBiMPs or TAK-063 during sperm selection resulted in higher recovery rates in comparison to the control, and these compounds effectively improved sperm motion in both fresh and cryopreserved samples with impaired motility. In conclusion, cBiMPs and TAK-063 exhibit potent and sustained effects on human sperm motility, enhancing the efficiency of sperm preparation techniques. The ability to improve sperm motility holds significant implications for male infertility treatment, facilitating the use of low complexity techniques such as intrauterine insemination or in vitro fertilization, and may also aid in selecting viable testicular sperm for intracytoplasmic sperm injection.

01 Feb 2025·Anesthesiology

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice

Article

Author: Lu, Ruirui ; Gerninghaus, Hannah ; Nagel, Chantal ; Hernandez-Olmos, Victor ; Petersen, Jonas ; Schmidtko, Achim ; Zhou, Fangyuan ; Metzner, Katharina ; Proschak, Ewgenij ; Gross, Tilman ; Sinderwald, Rekia ; Feil, Susanne ; Stehle, Daniel ; Feil, Robert ; Kallenborn-Gerhardt, Wiebke ; Duman, Emre

Background:Emerging evidence indicates that cyclic nucleotide phosphodiesterases exert distinct functions in pain processing and that targeting phosphodiesterases might be a novel strategy for pain relief. This study hypothesized that the phosphodiesterase isoform phosphodiesterase 10A (PDE10A) might be a target for analgesic therapy.Methods:In situ hybridization, immunostaining, cyclic nucleotide enzyme immunoassays, real-time cyclic guanosine monophosphate imaging, and real-time quantitative reverse transcription polymerase chain reaction were performed to investigate the expression and activity of PDE10A in the dorsal root ganglia and spinal cord. Mice of both sexes were assessed in multiple pain models after the administration of specific PDE10A inhibitors.Results:PDE10A is distinctly expressed in nociceptive neurons in the dorsal root ganglia and spinal cord of mice. Incubation of cultured sensory neurons with the PDE10A inhibitor, TAK-063 (150 nM), increased cyclic guanosine monophosphate levels in enzyme immunoassays and real-time imaging at the single-cell level. Strikingly, treatment with TAK-063 (0.3 mg/kg intraperitoneal) ameliorated the pain-like behavior of female and male mice in models of acute nociceptive pain after intraplantar injection of capsaicin (mean ± SD, 8.87 ± 8.78 s [TAK-063] vs. 51.24 ± 36.36 s [vehicle], P = 0.020) or allyl isothiocyanate (2.46 ± 3.43 s [TAK-063] vs. 10.36 ± 4.87 s [vehicle]; P = 0.018). Furthermore, TAK-063 (0.3 mg/kg intraperitoneal) reduced established pain-like behavior in models of inflammatory pain induced by intraplantar injection of zymosan (two-way ANOVA, group, F[1,18] = 48.51, TAK-063 vs. vehicle; P ≤ 0.0001) or complete Freund’s adjuvant (F[1,14] = 46.10, TAK-063 vs. vehicle; P ≤ 0.0001), without the development of antinociceptive tolerance. The antinociceptive effects were recapitulated using the PDE10A inhibitor PF-2545920.Conclusions:Collectively, the data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs.

01 Dec 2024·Molecular and Cellular Neuroscience

Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury

Article

Author: Dogan, Enes ; Kilic, Ertugrul ; Beker, Mustafa C ; Balaban, Buse ; Altintas, Mehmet O ; Beker, Mustafa C. ; Ozpinar, Aysenur ; Sengun, Nursena ; Bayraktaroglu, Cigdem ; Altunay, Serdar ; Altintas, Mehmet O.

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.

100 Deals associated with Balipodect

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External Link

KEGG	Wiki	ATC	Drug Bank
D11245	-	-	DB14774

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Phase 2	United States	Takeda Pharmaceutical Co., Ltd.	01 Jul 2015
Psychotic Disorders	Phase 2	United States	Takeda Pharmaceutical Co., Ltd.	01 Aug 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01892189 (Pubmed \| Psychopharmacology (Berl)) Manual	Phase 1	-	27	ketamine+TAK-063	xlsgnyazqu(bvmibwnzft) = brain activity hmgfhkimid (uclxkxmjip )	Positive	01 Feb 2020
NCT02477020 (Pubmed \| Schizophr Res) Manual	Phase 2	Schizophrenia	164	TAK-063	(kmswzbhxkq) = not achieved oqvbwclmth (xvzaxpuqhm ) View more	Negative	01 Feb 2019
				Placebo
NCT02477020 (Pubmed \| Basic Clin Pharmacol Toxicol)	Phase 2	Schizophrenia	164	TAK-063	(jciprtyksz) = vllcrwtsuu ctwvzokujb (ovunotlgty ) View more	-	01 Jun 2018
NCT02477020 (CTgov)	Phase 2	Schizophrenia	164	Placebo	knpieryvvm(kyblhgllka) = tboqhkehsz mogzqielmr (bnqkyslpez, mvxbxuayaj - oewiivlhky) View more	-	29 Sep 2017
NCT01892189 (CTgov)	Phase 1	Psychotic Disorders	27	placebo+TAK-063+ketamine (Placebo)	pixxyskmkl(kihtxaogmh) = btljjjqzrq meawtxxkid (zluytolkpi, wbjoboqvmp - phtwlvokqt) View more	-	12 Jan 2017
				TAK-063 (TAK-063 3 mg)	pixxyskmkl(kihtxaogmh) = royeoiozij meawtxxkid (zluytolkpi, cfxyngapuu - camtdqdjhh) View more
NCT01879722 (Pubmed) Manual	Phase 1	Schizophrenia	84	TAK-063	(hnvjsxonnf) = The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). qwiamyjgdz (olyltvchdc )	Positive	01 Oct 2016
				Placebo
NCT02370602 (CTgov)	Phase 1	-	13	TAK-063+[^11C]T-773 (TAK-063 3 mg + [^11C]T-773)	cxsrnbrxjw(hmmvotalkn) = pwwugkxkcv kbjafihmgn (hyptchextn, pkribpfyke - rvbfovtwbv) View more	-	20 Mar 2015
				TAK-063 (TAK-063 10 mg)	cxsrnbrxjw(hmmvotalkn) = unnrwavcnz kbjafihmgn (hyptchextn, eqofqqbwkn - wunrreqlni)