CD38 inhibitor 1 is a potent CD38 inhibitor with an IC50 value of 1.9nM for mouse CD38 [1]. CD38 inhibitor 1 can increase the level of NAD+, thereby activating various factors related to longevity and healthy lifespan, such as sirtuins, AMPK, and PARPs, to prevent metabolic dysfunction [2]. The CD38 inhibitor 1 has been widely used to protect the heart from damage caused by ischemic injury to endothelial cells and cardiomyocytes[3].
In vitro, CD38 inhibitor 1 treatment (1µM) for 14 days upregulated the expression of Col2 and aggrecan mRNA and promoted the differentiation of mouse chondrocytes[4]. Treatment with 50µM CD38 inhibitor 1 for 24 hours significantly inhibited the release of IL-1β and CXCL1 by mouse bone marrow-derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals[5]. Treatment with 20µM CD38 inhibitor 1 for 24 hours significantly induced the accumulation of extracellular cGAMP in ARH-77 cells[6].
In vivo, CD38 inhibitor 1 treatment via daily intraperitoneal injection at a dose of 10mg/kg twice a day for one month reduced white matter damage in the vascular dementia mouse model, improved cerebral blood flow, enhanced the expression of tight junction proteins in brain endothelial cells, and reduced neuroinflammation and blood-brain barrier (BBB) disruption[7].
References:
[1] Haffner C D, Becherer J D, Boros E E, et al. Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors[J]. Journal of medicinal chemistry, 2015, 58(8): 3548-3571.
[2] Tarragó M G, Chini C C S, Kanamori K S, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline[J]. Cell metabolism, 2018, 27(5): 1081-1095. e10.
[3] Boslett J, Reddy N, Alzarie Y A, et al. Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury[J]. The Journal of pharmacology and experimental therapeutics, 2019, 369(1): 55-64.
[4] Ma J, Ying J, Wang J, et al. CD38 drives progress of osteoarthritis by affecting cartilage homeostasis[J]. Orthopaedic Surgery, 2022, 14(5): 946-954.
[5] Alabarse P G, Oliveira P, Qin H, et al. The NADase CD38 is a central regulator in gouty inflammation and a novel druggable therapeutic target[J]. Inflammation Research, 2024, 73(5): 739-751.
[6] Cuollo L, Di Cristofano S, Sandomenico A, et al. CD38 restrains the activity of extracellular cGAMP in a model of multiple myeloma[J]. IScience, 2024, 27(5).
[7] Yu M, Qi Z, Zhang J, et al. Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia[J]. Journal of Pharmacological Sciences, 2025, 158(4): 310-321.
CD38 inhibitor 1是一种强效的CD38抑制剂，对小鼠CD38的IC50值为1.9nM[1]。CD38 inhibitor 1可增加NAD+水平，从而激活多种与长寿和健康寿命相关的因子，如sirtuins、AMPK和PARPs，以预防代谢功能障碍[2]。CD38 inhibitor 1已被广泛用于保护心脏免受缺血损伤对内皮细胞和心肌细胞的损害[3]。
在体外，1µM的CD38 inhibitor 1处理小鼠软骨细胞14天，上调了Col2和聚集蛋白聚糖mRNA的表达，并促进了细胞分化[4]。50µM的CD38 inhibitor 1处理小鼠骨髓来源的巨噬细胞(BMDMs)24小时，显著抑制了尿酸单钠(MSU)晶体刺激诱导的IL-1β和CXCL1释放[5]。20µM的CD38 inhibitor 1处理ARH-77细胞24小时，显著诱导了细胞外cGAMP的积累[6]。
在体内，腹腔注射10mg/kg剂量的CD38 inhibitor 1，每日两次，持续一个月，减轻了血管性痴呆小鼠模型中的白质损伤，改善了脑血流量，增强了脑内皮细胞中紧密连接蛋白的表达，并减轻了神经炎症和血脑屏障(BBB)破坏[7]。