A Phase 2, Multi-Centre, Randomised, Double Blind, Placebo Controlled Study Evaluating the Efficacy, Safety and Pharmacokinetics of Two Doses of a Candidate Disease Modifying Anti-Rheumatic Drug (DMARD), (SMP-114 120 mg and 240 mg Once Daily), Administered in Combination With Ongoing Methotrexate Treatment in Patients With Active Rheumatoid Arthritis.

To compare the efficacy of SMP-114 (120 and 240 mg/d) versus placebo in terms of the percentage of patients meeting the American College of Rheumatology criteria for 20% improvement in RA (ACR20) at week 24. The study hypothesis would be to demonstrate that the use of methotrexate and SMP-114 is more efficacious than Methotrexate alone.

Start Date01 Feb 2006

Sponsor / Collaborator

Dainippon Sumitomo Pharma Europe LTd.

100 Clinical Results associated with Rimacalib

100 Translational Medicine associated with Rimacalib

100 Patents (Medical) associated with Rimacalib

Literatures (Medical) associated with Rimacalib

20 Dec 2024·Journal of Biomolecular Structure and Dynamics

Structure-based virtual screening and molecular docking approaches to identify potential inhibitors against KIF2C to combat glioma

Article

Author: Hussein, Deema ; AlAjmi, Mohamed F. ; Rehman, Md Tabish ; Al Zughaibi, Torki ; Haque, Shafiul ; Alghamdi, Fahad ; Baeesa, Saleh ; Bangash, Mohammed ; Saka, Mohamad

Glioma, a kind of malignant brain tumor, is extremely lethal. Kinesin family member 2C (KIF2C) was found to have an aberrant expression in several cancer types, including lung cancer and glioma. KIF2C may therefore be a useful therapeutic target for the treatment of glioma. In the current study, new drug candidates that may function as KIF2C enzyme inhibitors were discovered. MTi OpenScreen was used to carry out the structure-based virtual screening of an inbuilt drug library containing 150,000 compounds. These compounds belong to different classes, such as natural product-based compounds (NP-lib), purchasable approved drugs (Drugs-lib), and food constituents compound collection (FOOD-lib). Based on their binding affinities, a total of 84 compounds were further pushed to calculate ADMET properties. The compounds (16) meeting the ADMET cutoff ranges were then further docked to the receptor to find their plausible binding modes using the Glide tool's standard precision (SP) technique. The docking results were examined using the Glide gscore, and the best binding compounds (Rimacalib and Sarizotan) were chosen to test their stability with KIF2C protein through molecular dynamics (MD) simulation. Similarly, Principal Component Analysis and cross-correlation matrix were also examined. The MM/GBSA binding free energies showed a considerable energy contribution in the binding of hits with the KIF2C. Collectively, these findings strongly suggest the potential of the lead compounds to inhibit the biological function of KIF2C, emphasizing the need for further investigation in this area.Communicated by Ramaswamy H. Sarma.

01 Sep 2018·The FEBS JournalQ3 · BIOLOGY

Structure‐based design and molecular profiling of Smac‐mimetics selective for cellular IAPs

Q3 · BIOLOGY

Article

Author: Seneci, Pierfausto ; de Rosa, Matteo ; Corti, Alessandro ; Cossu, Federica ; Milani, Mario ; Mastrangelo, Eloise ; Lecis, Daniele

Inhibitor of Apoptosis Proteins (IAPs) is highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds (Smac‐mimetics, SMs) have been developed to inhibit IAPs prosurvival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologs play distinctive roles in cancer cell survival and immunomodulation, SM‐induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto‐ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the noncanonical NF‐κB pathway. For this reason, we started the BIR3‐driven design of compounds selective for cIAP1 and with reduced affinity for X‐linked IAP (XIAP), in order to focus SMs antitumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1‐selective SM (SM130 and SM114, respectively). The two SMs displayed 23‐ and 32‐fold higher affinity for cIAP1‐BIR3 over XIAP‐BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell‐based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases‐3, ‐8, and ‐9‐independent cIAP1 degradation. The design of cIAPs‐selective compounds represents an innovative approach in the field of anticancer drugs development, being useful to elucidate different prosurvival mechanisms and to reduce the adverse effects of pan‐IAPs compounds in cancer therapy.DatabaseStructural data are available in the Protein Data Bank database under the accession codes 6EXW (cIAP1‐BIR3/SM130 complex) and 6EY2 (XIAP‐BIR3/SM114 complex).

01 Jul 2017·Basic Research in CardiologyQ1 · MEDICINE

Reduction of SR Ca2+ leak and arrhythmogenic cellular correlates by SMP-114, a novel CaMKII inhibitor with oral bioavailability

Q1 · MEDICINE

Article

Author: Zwenger, Anne ; Neef, Stefan ; Mann, Christian ; Dybkova, Nataliya ; Maier, Lars S

Sarcoplasmic reticulum (SR) Ca²⁺ leak induced by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is centrally involved in atrial and ventricular arrhythmogenesis as well as heart failure remodeling. Consequently, treating SR Ca²⁺ leak has been proposed as a novel therapeutic paradigm, but compounds for use in humans are lacking. SMP-114 ("Rimacalib") is a novel, orally available CaMKII inhibitor developed for human use that has already entered clinical phase II trials to treat rheumatoid arthritis. We speculated that SMP-114 might also be useful to treat cardiac SR Ca²⁺ leak. SMP-114 significantly reduces SR Ca²⁺ leak (as assessed by Ca²⁺ sparks) in human atrial (0.72 ± 0.33 sparks/100 µm/s vs. control 3.02 ± 0.91 sparks/100 µm/s) and failing left ventricular (0.78 ± 0.23 vs. 1.69 ± 0.27 sparks/100 µm/s) as well as in murine ventricular cardiomyocytes (0.30 ± 0.07 vs. 1.50 ± 0.28 sparks/100 µm/s). Associated with lower SR Ca²⁺ leak, we found that SMP-114 suppressed the occurrence of spontaneous arrhythmogenic spontaneous Ca²⁺ release (0.356 ± 0.109 vs. 0.927 ± 0.216 events per 30 s stimulation cessation). In consequence, post-rest potentiation of Ca²⁺-transient amplitude (measured using Fura-2) during the 30 s pause was improved by SMP-114 (52 ± 5 vs. 37 ± 4%). Noteworthy, SMP-114 has these beneficial effects without negatively impairing global excitation-contraction coupling: neither systolic Ca²⁺ release nor single cell contractility was compromised, and also SR Ca²⁺ reuptake, in line with resulting cardiomyocyte relaxation, was not impaired by SMP-114 in our assays. SMP-114 demonstrated potential to treat SR Ca²⁺ leak and consequently proarrhythmogenic events in rodent as well as in human atrial cardiomyocytes and cardiomyocytes from patients with heart failure. Further research is necessary towards clinical use in cardiac disease.

100 Deals associated with Rimacalib

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	Hungary	Dainippon Sumitomo Pharma Europe LTd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Germany	Sumitomo Pharma Co., Ltd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	United Kingdom	Dainippon Sumitomo Pharma Europe LTd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	United Kingdom	Sumitomo Pharma Co., Ltd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Germany	Dainippon Sumitomo Pharma Europe LTd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Hungary	Sumitomo Pharma Co., Ltd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Poland	Sumitomo Pharma Co., Ltd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Czechia	Dainippon Sumitomo Pharma Europe LTd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Netherlands	Sumitomo Pharma Co., Ltd.	01 Feb 2006
Rheumatoid Arthritis	Phase 2	Poland	Dainippon Sumitomo Pharma Europe LTd.	01 Feb 2006

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