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

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 ; Maier, Lars S ; Dybkova, Nataliya

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.

01 Dec 2010·BMC Musculoskeletal DisordersQ3 · MEDICINE

Expression and regulation of HIF-1alpha in macrophages under inflammatory conditions; significant reduction of VEGF by CaMKII inhibitor

Q3 · MEDICINE

ArticleOA

Author: Miek A. van Leeuwen ; Cees G. M. Kallenberg ; Berber Doornbos-van der Meer ; Johanna Westra ; Ingrid A. M. van Roosmalen ; Marcel D. Posthumus ; Elisabeth Brouwer

BACKGROUNDMacrophages expressing the pro-angiogenic transcription factor hypoxia-inducible factor (HIF)-1alpha have been demonstrated in rheumatoid arthritis (RA) in the synovial tissue. Aim of the present study was to investigate intracellular signal transduction regulation of pro-inflammatory HIF-1 alpha expression in macrophages to identify possible new intervention strategies. We investigated the effects of CaMKII-inhibitors amongst other kinase inhibitors, on HIF-1 alpha expression and downstream production of pro-angiogenic factors in macrophages.METHODSDifferentiated THP-1 cells and synovial fluid (SF) macrophages were stimulated with 1 microg/ml LPS with or without pretreatment with specific inhibitors of the ERK pathway (PD98059), the PI3K pathway (LY294002), and the CaMKII pathway (KN93 and SMP-114). mRNA and protein expression of HIF-1 alpha, VEGF, MMP-9, and IL-8 was measured in cell lysates and cell supernatants.RESULTSHIF-1 alpha protein expression in LPS-stimulated THP-1 macrophages could be blocked by ERK- and PI3K-inhibitors, but also by the CaMKII inhibitor KN93. THP-1 and SF macrophages produced high levels of VEGF, IL-8, and MMP-9, and VEGF protein production was significantly inhibited by PI3K-inhibitor, and by both CaMKII inhibitors. LPS stimulation in an hypoxic environment did not change VEGF levels, suggesting that LPS induced VEGF production in macrophages is more important than the hypoxic induction.CONCLUSIONSExpression of HIF-1 alpha and downstream effects in macrophages are regulated by ERK-, PI3K, but also by CaMKII pathways. Inhibition of HIF-1alpha protein expression and significant inhibition of VEGF production in macrophages was found using CaMKII inhibitors. This is an unknown but very interesting effect of the CaMKII inhibitor SMP-114, which has been in clinical trial as DMARD for the treatment of RA. This effect may contribute to the anti-arthritic effects of SMP-114.

100 Deals associated with Rimacalib

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	-	-	-
Rheumatoid Arthritis	Phase 2	JP	-	-

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