Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.

开始日期2022-11-25

申办/合作机构

BAR Pharmaceuticals s.r.l.

100 项与 BAR-502 相关的临床结果

登录后查看更多信息

100 项与 BAR-502 相关的转化医学

登录后查看更多信息

100 项与 BAR-502 相关的专利（医药）

登录后查看更多信息

项与 BAR-502 相关的文献（医药）

2023-01-01·Frontiers in oncology

Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.

Article

作者: Ricci, Patrizia ; Fiorucci, Stefano ; Zampella, Angela ; Massa, Carmen ; Distrutti, Eleonora ; Rosselli, Rosalinda ; Bellini, Rachele ; Rapacciuolo, Pasquale ; Urbani, Ginevra ; Lupia, Antonio ; Morretta, Elva ; Di Giorgio, Cristina ; Moraca, Federica ; Marchianò, Silvia ; Biagioli, Michele ; Sepe, Valentina ; Monti, Maria Chiara ; Bordoni, Martina ; Catalanotti, Bruno

IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC₅₀ of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

2022-11-02·Expert Opinion on Therapeutic Targets

Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease?

Article

作者: Małyszko, Jacek ; Małyszko, Jolanta ; Zuzda, Konrad ; Grycuk, Wiktoria

INTRODUCTIONAltered lipid distribution and metabolism may lead to the development and/or progression of chronic kidney disease (CKD). Dyslipidemia is a major risk factor for CKD and increases the risk of cardiovascular events and mortality. Therefore, lipid-lowering treatments may decrease cardiovascular risk and prevent death.AREAS COVEREDKey players involved in regulating lipid accumulation in the kidney; contribution of lipids to CKD progression, lipotoxicity, and mitochondrial dysfunction in kidney disease; recent therapeutic approaches for dyslipidemia.EXPERT OPINIONThe precise mechanisms for regulating lipid metabolism, particularly in kidney disease, are poorly understood. Guidelines for lipid-lowering therapy for CKD are controversial. Several hypolipemic therapies are available, but compared to others, statin therapy is the most common. No clinical trial has evaluated the efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in preventing cardiovascular events or improving kidney function among patients with CKD or kidney transplant recipients. Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases.

2022-11-01·European Journal of Medicinal Chemistry

Development of 3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate sodium salt (INT-767): Process optimization, synthesis and characterization of metabolites

Article

作者: Gioiello, Antimo ; Passeri, Daniela ; Pellicciari, Roberto ; Lozza, Anna Maria ; Macchiarulo, Antonio ; Baxendale, Ian R ; Venturoni, Francesco ; Cerra, Bruno ; Souma, Maria ; Ceccarelli, Giada ; De Franco, Francesca

Herein we report our synthetic efforts in supporting the development of the bile alcohol sulfate INT-767, a FXR/TGR5 dual agonist with remarkable therapeutic potential for liver disorders. We describe the process development to a final route for large scale preparation and analogues synthesis. Key sequences include Grignard addition, a one-pot two-step shortening-reduction of the carboxylic side chain, and the final sulfation reaction. The necessity for additional steps such as the protection/deprotection of hydroxyl groups at the steroidal body was also evaluated for step-economy and formation of side-products. Critical bottlenecks such as the side chain degradation have been tackled using flow technology before scaling-up individual steps. The final synthetic route may be successfully employed to produce the amount of INT-767 required to support late-stage clinical development of the compound. Furthermore, potential metabolites have been synthesized, characterized and evaluated for their ability to modulate FXR and TGR5 receptors providing key reference standards for future drug investigations, as well as offering further insights into the structure-activity relationships of this class of compounds.

100 项与 BAR-502 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
代谢功能障碍相关的脂肪肝病	申请上市	葡萄牙	BAR Pharmaceuticals s.r.l.	2022-11-25
非酒精性脂肪性肝炎	临床前	葡萄牙	Bär GmbH	-