Author: Xu, Yan ; Song, Wei ; Chen, Yubai ; Li, Wen ; Wu, Liuying ; Chen, Yong ; Chen, Yuhan ; Peng, Zhihong ; Liang, Meiyu ; Yu, Qin ; Yang, Zhiming ; Yan, Xingting

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.

01 Nov 2023·European review for medical and pharmacological sciences

Pharmacological activity and clinical progress of Triptolide and its derivatives LLDT-8, PG490-88Na, and Minnelide: a narrative review.

Review

Author: Cao, L ; Zeng, L-S ; Yang, P ; He, W-H ; Qin, Y-Y

Triptolide, a compound isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. Due to its interesting structural features and diverse pharmacological activities, it has attracted great interest by the Society of Organic Chemistry and Pharmaceutical Chemistry. However, its clinical potential is greatly hampered by limited aqueous solubility and oral bioavailability, and multi-organ toxicity. In recent years, various derivatives of Triptolide have made varying degrees of progress in the treatment of inflammatory diseases, autoimmune diseases, and cancer. The most researched and potentially clinically valuable of them were (5R)-5-hydroxytriptolide (LLDT-8), PG490-88Na (F6008), and Minnelide. In this review, we provide an overview of the advancements made in triptolide and several of its derivatives' biological activity, mechanisms of action, and clinical development. We also summarized some prospects for the future development of triptolide and its derivatives. It is hoped to contribute to a better understanding of the progress in this field, make constructive suggestions for further studies of Triptolide, and provide a theoretical reference for the rational development of new drugs.

01 Mar 2019·International ImmunopharmacologyQ2 · MEDICINE

PG490-88, a derivative of triptolide, suppresses ischemia/reperfusion-induced lung damage by maintaining tight junction barriers and targeting multiple signaling pathways

Q2 · MEDICINE

Article

Author: Huang, Kun-Lun ; Wu, Shu-Yu ; Liao, Wen-I ; Chu, Shi-Jye ; Pao, Hsin-Ping ; Hung, Kuei-Yi

Previous studies demonstrated that triptolide (PG490) has many anti-inflammatory and immunosuppressive effects. However, little is known about the effect of PG490-88 (a water-soluble derivative of triptolide) on ischemia/reperfusion (I/R)-induced acute lung injury. We assessed the effects of PG490-88 on I/R-induced acute lung injury in rats and on hypoxia/reoxygenation (H/R) in a line of murine epithelial cells. Isolated perfused rat lungs were subjected to 40 min of ischemia, followed by 60 min of reperfusion to induce I/R injury. Induction of I/R led to lung edema, elevated pulmonary arterial pressure, histological evidence of lung inflammation, oxidative stress, and increased levels of TNF-α and CINC-1 in bronchoalveolar lavage fluid. PG490-88 significantly suppressed all of these responses. Additionally, induction of I/R reduced the expression of claudin-4, occludin, and ZO-1, and increased apoptosis in lung tissue. PG490-88 also significantly suppressed these effects. I/R reduced the levels of IκB-α and MKP-1, and increased the levels of nuclear NF-κB and mitogen-activated protein kinase in lung tissue, and PG490-88 suppressed these effects. In vitro studies using mouse lung alveolar epithelial cells indicated that H/R increased the levels of phosphorylated p65 and MIP-2, but decreased the level of IκB-α. PG490-88 also suppressed these effects. In I/R damaged lungs, PG490-88 suppresses the inflammatory response, disruption of tight junction structure, and apoptosis. PG490-88 has the potential as a prophylactic agent to prevent I/R-induced lung injury.

100 Deals associated with Omtriptolide sodium

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KEGG	Wiki	ATC	Drug Bank
D06625	-	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Myeloid Leukemia	Phase 3	FR	-	-
Solid tumor	Phase 3	US	Oxford PharmaGenesis Ltd.	-
Graft vs Host Disease	Phase 2	US	Oxford PharmaGenesis Ltd.	-
Myeloid Leukemia	Phase 1	-	Stanford University	-
Myeloid Leukemia	Phase 1	-	Pharmagenesis, Inc.	-
Myeloid Leukemia	Phase 1	-	Duke University	-
Myeloid Leukemia	Phase 1	-	Pierre Fabre SA	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


5R01DK074835-04 (ASN2013)	Not Applicable	Acute Kidney Injury	-	PG490-88	bbsncxmrmz(luiqfvdzwy) = nynnvhuavi ixyfnnoodb (tncqlaextf ) View more	Positive	05 Nov 2013
				Cisplatin	zpqkuckjjx(tzwgdzxasu) = wooagzfijk fhspbrjfic (bzdqxgfsnq ) View more

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