The purpose of this study is to assess the extent and rate of absorption of LY2140023 in healthy participants. The study has two periods. In Treatment Period 1, participants will receive a single oral dose of 80 milligrams (mg) LY2140023 followed by a 2-hour intravenous (IV) infusion of approximately 100 micrograms (µg) LY2140023 containing approximately 100 nanocuries (nCi) [14C]-LY2140023. In Treatment Period 2, participants will receive an oral dose of 80 mg LY2140023 followed by a 2-hour IV infusion of approximately 100 µg LY404039 containing approximately 100 nCi [14C]-LY404039. There will be at least a 3-day washout between doses.

Start Date01 Jul 2012

Sponsor / Collaborator

Denovo Biopharma LLC

100 Clinical Results associated with LY-404039

100 Translational Medicine associated with LY-404039

100 Patents (Medical) associated with LY-404039

Literatures (Medical) associated with LY-404039

05 Nov 2024·Proceedings of the National Academy of Sciences

Deficiency of DDX3X results in neurogenesis defects and abnormal behaviors via dysfunction of the Notch signaling

Article

Author: Duan, Weicheng ; Liu, Jiahui ; Sui, Yang ; Huang, Guiyang ; Xiong, Bo ; Chen, Liangpei ; Cao, Xu ; Yu, Yuxin ; Wang, Kang ; Chu, Xufeng ; Eichler, Evan E.

The molecular mechanisms underlying the neurodevelopmental disorders (NDDs) caused by DDX3X variants remain poorly understood. In this study, we validated that de novo DDX3X variants are enriched in female developmental delay (DD) patients and mainly affect the evolutionarily conserved amino acids based on a meta-analysis of 46,612 NDD trios. We generated a ddx3x deficient zebrafish allele, which exhibited reduced survival rate, DD, microcephaly, adaptation defects, anxiolytic behaviors, social interaction deficits, and impaired spatial recognitive memory. As revealed by single-nucleus RNA sequencing and biological validations, ddx3x deficiency leads to reduced neural stem cell pool, decreased total neuron number, and imbalanced differentiation of excitatory and inhibitory neurons, which are responsible for the behavioral defects. Indeed, the supplementation of L-glutamate or glutamate receptor agonist ly404039 could partly rescue the adaptation and social deficits. Mechanistically, we reveal that the ddx3x deficiency attenuates the stability of the crebbp mRNA, which in turn causes downregulation of Notch signaling and defects in neurogenesis. Our study sheds light on the molecular pathology underlying the abnormal neurodevelopment and behavior of NDD patients with DDX3X mutations, as well as providing potential therapeutic targets for the precision treatment.

01 Nov 2024·Naunyn-Schmiedeberg's Archives of Pharmacology

Effect of mGluR2 and mGluR2/3 activators on parkinsonism in the MPTP-lesioned non-human primate

Article

Author: Kwan, Cynthia ; Frouni, Imane ; Kang, Woojin ; Huot, Philippe ; Nuara, Stephen G ; Bédard, Dominique ; Gourdon, Jim C ; Hamadjida, Adjia ; Belliveau, Sébastien

We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR₂) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR_2/3) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR_2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR₂ positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR₂ positive allosteric modulation and combined mGluR_2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.

01 Mar 2024·Neurochemical Research

Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HT2AR-Mediated Gs Signaling Pathway

Article

Author: Liu, Xiaoqian ; Gao, Huan ; Su, Ruibin ; Xie, Lulu ; Tan, Bo

Hallucinogenic 5-HT_2A receptor (5-HT_2AR) agonists-induced head-twitch response (HTR) is regulated by G_s signaling pathway. Formation of heterodimers between 5-HT_2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT_2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT_2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced G_q and G_s activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT_2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT_2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT_2AR-mediated G_s signaling pathway. In HEK-293T cells co-expressing 5-HT_2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT_2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.

100 Deals associated with LY-404039

External Link

KEGG	Wiki	ATC	Drug Bank
-	LY-404039	-	-

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Phase 2	US	Eli Lilly & Co.	02 Sep 2007

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01637142 (CTgov)	Phase 1	-	18	[14C]-LY2140023+LY2140023 (Oral 80 mg LY2140023 and IV LY2140023/[14C]-LY2140023)	oehshcqxqo(vzleikgnwk) = hkaqhwfulj demfeepugm (zhjdjcpqcz, jiwfuacpgw - cadhlnyluy) View more	-	21 Sep 2021
				[14C]-LY404039+LY404039+LY2140023 (Oral 80 mg LY2140023 and IV LY404039/[14C]-LY404039)	eqdbsjkdcx(zdebfxwukt) = nkqlzeqppr basjxcdzvr (flrpnriphq, qhazkfqnsi - kfdynpxwdm) View more

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

LY-404039

Overview

Basic Info

Structure

Related

External Link

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation