A Double Blind, Randomized, Phase II-III Maintenance Study of SR48692 Versus Placebo in Patients With Extensive Stage Small Cell Lung Cancer Following a First Line Chemotherapy With Cisplatin + Etoposide

To demonstrate an increase in overall survival for patients with newly diagnosed extended stage small cell lung cancer when treated with SR48692 versus placebo, after an initial response (complete or partial response or stable) to first line cisplatin plus etoposide.
Primary objective: comparison of overall survival between patients in the control arm and the meclinertant arm.
Secondary objectives: comparison of the progression free survival, the time to progression, the clinical benefit, the quality of life, the toxicity and safety between patients in the control arm and the meclinertant arm.

Start Date01 Oct 2002

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with Meclinertant

100 Translational Medicine associated with Meclinertant

100 Patents (Medical) associated with Meclinertant

261

Literatures (Medical) associated with Meclinertant

01 Oct 2024·International Journal of Biological Macromolecules

Revealing the graded activation mechanism of neurotensin receptor 1

Article

Author: Hu, Jianping ; Zhang, Xinyu ; Su, Jingjie ; Wu, Zhixiang ; Sun, Xiaohan ; Li, Chunhua

Graded activation contributes to the precise regulation of GPCR activity, presenting new opportunities for drug design. In this work, a total of 10 μs enhanced-sampling simulations are performed to provide molecular insights into the binding dynamics differences of the neurotensin receptor 1 (NTSR1) to the full agonist SRI-9829, partial agonist RTI-3a and inverse agonist SR48692. The possible graded activation mechanism of NTSR1 is revealed by an integrated analysis utilizing the reweighted potential of mean force (PMF), deep learning (DL) and transfer entropy (TE). Specifically, the orthosteric pocket is observed to undergo expansion and contraction, with the G-protein-binding site experiencing interconversions among the inactive, intermediate and active-like states. Detailed structural comparisons capture subtle conformational differences arising from ligand binding in allosteric signaling, which can well explain the graded activation. Critical microswitches that contribute to graded activation are efficiently identified with the DL model. TE calculations enable the visualization of allosteric communication networks within the receptor, elucidating the driver-responder relationships associated with signal transduction. Fortunately, the dissociation of the full agonist from the orthosteric pocket is observed. The current findings systematically reveal the mechanism of NTSR1 graded activation, and also provide implications for structure-based drug design.

15 Jan 2024·The FASEB Journal

Integrating network pharmacology and transcriptomic omics reveals that akebia saponin D attenuates neutrophil extracellular traps‐induced neuroinflammation via NTSR1/PKAc/PAD4 pathway after intracerebral hemorrhage

Article

Author: Chen, Yihao ; Ye, Liguo ; Chang, Jianbo ; Wang, Renzhi ; Deng, Congcong ; Gu, Lingui ; Feng, Ming ; Wei, Junji ; Bao, Xinjie ; Zhang, Xin

AbstractNeutrophils and their production of neutrophil extracellular traps (NETs) significantly contribute to neuroinflammation and brain damage after intracerebral hemorrhage (ICH). Although Akebia saponin D (ASD) demonstrates strong anti‐inflammatory activities and blood–brain barrier permeability, its role in regulating NETs formation and neuroinflammation following ICH is uncharted. Our research focused on unraveling the influence of ASD on neuroinflammation mediated by NETs and the mechanisms involved. We found that increased levels of peripheral blood neutrophils post‐ICH are correlated with worse prognostic outcomes. Through network pharmacology, we identified ASD as a promising therapeutic target for ICH. ASD administration significantly improved neurobehavioral performance and decreased NETs production in neutrophils. Furthermore, ASD was shown to upregulate the membrane protein NTSR1 and activate the cAMP signaling pathway, confirmed through transcriptome sequencing, western blot, and immunofluorescence. Interestingly, the NTSR1 inhibitor SR48692 significantly nullified ASD's anti‐NETs effects and dampened cAMP pathway activation. Mechanistically, suppression of PKAc via H89 negated ASD's anti‐NETs effects but did not affect NTSR1. Our study suggests that ASD may reduce NETs formation and neuroinflammation, potentially involving the NTSR1/PKAc/PAD4 pathway post‐ICH, underlining the potential of ASD in mitigating neuroinflammation through its anti‐NETs properties.

01 Jan 2024·Reproductive Toxicology

Neurotensin receptor-1 antagonist SR48692 modulation of high-fat diet induced reproductive impairment in male mice

Article

Author: Pal, Himanshu ; Mohanty, Banalata ; Verma, Pradeep

Neurotensin (NTS), a tridecapeptide of the gastrointestinal tract, has been implicated in the facilitation of lipid absorption on ingestion of a high-fat diet (HFD) especially via NTS receptors, NTSR1, NTSR2, and NTSR3, to cause lipid metabolic dysregulation and imbalance of the oxidant-antioxidant system. Oxidative stress induced a negative impact on reproductive function, affecting the reproductive organ and related reproductive hormones. The present study elucidated the efficacy of NTSR1 antagonist SR48692 in the modulation of HFD-induced reproductive impairment in male mice. Swiss albino mice (male, 23 ± 2 g) were maintained (6/group) for eight weeks; Group-I chow diet (CD), Group-II HFD, Group-III (HFD+SR48692_L), Group-IV (HFD+SR48692_H), Group-V (CD+SR48692_L) and Group-VI (CD+SR48692_H). SR48692 low (100 µg/kg b.w./SR48692_L) and high-dose (400 µg/kg b.w./SR48692_H) were given intraperitoneally for the last four weeks. Treatment with low-dose (SR48692_L) to HFD-fed mice showed some efficacy in mitigating lipid dysregulation, oxidative stress, and reproductive impairment as evidenced by decreased triglycerides, total cholesterol, low-density lipoprotein cholesterol, leptin, and increased high-density lipoprotein cholesterol, increased antioxidant defense enzymes, reduction of histopathological scores in testis and increase in plasma level of LH, FSH and testosterone compared to that of HFD, but not up to CD. With the high-dose of antagonist (SR48692_H) showed more adverse effects even from that of HFD. Treatment of both doses of SR48692 to CD-fed mice these effects become more extended. Less effectiveness of NTSR1 antagonist with the doses tried (low and high) in normalizing the lipid dysregulation and reproductive impairments might be due to the persistence of NTSR2/NTSR3-mediated lipid absorption.

100 Deals associated with Meclinertant

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Indication	Highest Phase	Country/Location	Organization	Date
Extensive stage Small Cell Lung Cancer	Discovery	NL	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	RU	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	FR	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	MX	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	ES	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	BR	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	IT	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	HU	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	PL	Sanofi	01 Oct 2002
Extensive stage Small Cell Lung Cancer	Discovery	AR	Sanofi	01 Oct 2002

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