SAR-100842 is a potent, selective oral antagonist of the LPAR1, for diffuse cutaneous systemic sclerosis [1]. SAR-100842 is safe, moderately effective, and well-tolerated in patients [1].
SAR-100842(10 μM) showed weak inhibitory activity (25-30%) on the impact on Gαq signal transduction in an RH7777 cell line exogenously expressing the LPA1 receptor. SAR-100842 was able to fully inhibit the LPA driven Gαi signaling with an IC50 of 52.5 ± 12 nM. SAR-100842 (IC50 31 ± 8.5 nM) fully inhibited the LPA mediated G-protein signalling subsequently leads to recruitment and activation of β-arrestin. SAR-100842 showed a significant inhibition of Gα12/13 signalling at 1 and 10 μM in MeT-5A cell line [2]. 50 μM SAR-100842 reduced the migration of MDA-MD-231T cells through a collagen membrane to FBS and LPA chemoattractants, respectively. In 4T1-Luc2 cells 50 μM SAR-100842 reduced migration to FBS and LPA, respectively [3].
SAR-100842 (30 mg/kg BID) reversed significantly dermal thickness, inhibited myofibroblast differentiation and skin collagen content in the mouse model of bleomycin-induced skin fibrosis. SAR-100842 significantly reduced the expression of CXCL-1 and IL-13, associated with the TH-2 cytokine milieu found in Systemic Sclerosis (SSc) [4]. SAR-100842 has a half-life of 4.9 h and a Cmax of 5600 ng/mL after a 30 mg/kg oral dosing in mice [1].
References:
[1]. Allanore Y, Distler O, Jagerschmidt A, et al. Lysophosphatidic acid receptor 1 antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis: a double‐blind, randomized, eight‐week placebo‐controlled study followed by a sixteen‐week open‐label extension study[J]. Arthritis & Rheumatology, 2018, 70(10): 1634-1643.
[2]. Ellery J, Dickson L, Cheung T, et al. Identification of compounds acting as negative allosteric modulators of the LPA1 receptor[J]. European journal of pharmacology, 2018, 833: 8-15.
[3]. Brooks D, Zimmer A, Wakefield L, et al. Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target[J]. Oncotarget, 2018, 9(34): 23462.
[4]. Illiano S, Ledein L, Bidouard J P, et al. OP0228 Protective Effect of LPA1 and 3 Receptor Antagonism in Experimental Skin Fibrosis is Linked to LPA Activity in Dermal Fibroblasts of SSC Patients[J]. Annals of the Rheumatic Diseases, 2013, 72(Suppl 3): A129-A129.
SAR-100842 是一种有效的选择性 LPAR1 口服拮抗剂，用于治疗弥漫性皮肤系统性硬化症[1]。 SAR-100842 对患者安全、有效且耐受性良好[1]。
SAR-100842(10 μM) 对外源表达 LPA1 受体的 RH7777 细胞系中 Gαq 信号转导的影响显示出较弱的抑制活性 (25-30%)。 SAR-100842 能够完全抑制 LPA 驱动的 Gαi 信号，IC50 为 52.5 ± 12 nM。 SAR-100842 (IC50 31 ± 8.5 nM) 完全抑制 LPA 介导的 G 蛋白信号传导，随后导致 β-arrestin 的募集和激活。在 MeT-5A 细胞系 [2] 中，SAR-100842 在 1 和 10 μM 时显示出对 Gα12/13 信号的显着抑制。 50 μM SAR-100842 减少了 MDA-MD-231T 细胞通过胶原蛋白膜分别向 FBS 和 LPA 趋化剂的迁移。在 4T1-Luc2 细胞中，50 μM SAR-100842 分别减少了向 FBS 和 LPA 的迁移[3]。
在博来霉素诱导的皮肤纤维化小鼠模型中，SAR-100842（30 mg/kg BID）显着逆转真皮厚度，抑制肌成纤维细胞分化和皮肤胶原蛋白含量。 SAR-100842 显着降低了与系统性硬化症 (SSc) [4] 中发现的 TH-2 细胞因子环境相关的 CXCL-1 和 IL-13 的表达。 SAR-100842 在小鼠中口服 30 mg/kg 后的半衰期为 4.9 小时，Cmax 为 5600 ng/mL[1]。