TOP-N53: A Clinical Drug Candidate for the Treatment of Non-healing Wounds

Abstract

Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite of improvements in standards of care there are no effective and safe treatments that promote new tissue formation and wound closure in ailments such as diabetic foot ulcer, pressure ulcer, venous leg ulcer or digital ulcer in systemic sclerosis. Endothelial dysfunction, which associates with impaired endogenous nitric oxide formation is assumed to be a main disease mechanism in chronic, non-healing wounds in diabetic and elderly patients as well as in digital ulcers in systemic sclerosis. Topadur Pharma has invented small molecular weight nitric oxide-releasing PDE5 inhibitors, which by modulating a key enzyme system of intracellular signaling may address chronic non-healing wounds. The promising first drug candidate TOP-N53 is currently in early clinical development. Here we describe for the first time the design of TOP-N53 and the synthesis of the clinical GMP batch.

Raynaud's phenomenon and digital ulcers: advances in evaluation and management

“…It is hoped that recent systematic reviews on topical nitrates [57,58] ] reported a preclinical study investigating the formulation of a novel nifedipine cream stable to ultraviolet light. Topical PDE5 inhibitors are also being researched [63,64] and topical econazole nitrate, an antagonist of Transient Receptor Potential Melastatin 8 has been studied in vitro [61,66 & ]. These are all important steps forward towards long-awaited clinical trials of topical treatments.…”

“…Although the use of topical glyceryl trinitrate for Raynaud's phenomenon was suggested as far back as 1951 [56], progress with topical therapies has been very slow. It is hoped that recent systematic reviews on topical nitrates [57,58] herald a wave of new interest, with several publications on topical therapies over the last 3 years [59–61,62 ▪ ,63–65,66 ▪ ]. Wasan et al [62 ▪ ] reported a preclinical study investigating the formulation of a novel nifedipine cream stable to ultraviolet light.…”

Topical Wound Treatment with a Nitric Oxide-Releasing PDE5 Inhibitor Formulation Enhances Blood Perfusion and Promotes Healing in Mice

“…When formulated in a liquid hydrogel, this compound can be used for topical application on wounds. Hydrogel formulations as presented in this study will be particularly suitable for wounds that allow a daily treatment, such as digital ulcers that result from poor blood flow due to vasoconstriction in systemic sclerosis patients [36]. Therefore, the results presented here encourage further translational research, including the development of delivery systems that allow application of TOP-N53 in a time-controlled manner and appropriate dose for improved treatment of chronic, non-healing skin wounds.…”

Therapeutic potential of nitric oxide in vascular aging due to the promotion of angiogenesis

“…Sildenafil is a phosphodiesterase type 5 (PED5) inhibitor, and the compound TOP‐N53 (Figure 3) was obtained by introducing NO donor based on its PED5 inhibitor structure, which improves intracellular cGMP levels through NO release, restores microcirculation in wound tissues, and promotes angiogenesis. Currently, TOP‐N53 is used for the therapy of impaired wound healing caused by diabetes and is in phase I clinical trials (Ben‐Yehuda Greenwald et al, 2021; Naef et al, 2020). In addition, the NO‐aspirin hybrid drug NCX 4016 (Figure 3) significantly reduced endothelial cell apoptosis, promoted reparative vascular angiogenesis, and attenuated the effects of secondary arterial occlusion more effectively compared to aspirin alone (Emanueli et al, 2004).…”