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Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Since inhibitors of human PDEs, like cilomilast, piclamilast, sildenafil and tadalafil were known, design efforts were often focused on repurposing these drugs and developing analogs thereof (Amata et al. 2014, Ochiana et al. 2012, Wang et al. 2012, Woodring et al. 2013), but with rather limited success. For example, Amata et al. (2014) found that cilomilast 143 (Figure 52) had an IC50 of 16.4 μM against TbPDEB1 and the best derivative 144 (Figure 52) resulted in an IC50 of 0.95 μM. However, the EC50 of 144 in a cellular assay against T. brucei was still only modest (26 μM vs. cilomilast 143 EC50 > 50 μM). Structures of the human PDE inhibitor cilomilast 143 and its derivative 144 optimized for TbPDEB1 targeting.
Phosphodiesterase‑4 inhibitors: a review of current developments (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Zhihao Liu, Mingjian Liu, Zhenqing Cao, Pengsen Qiu, Gaopeng Song
LEO 29102 (35) is a potent and highly selective PDE4 inhibitor with an IC50 value of 5 nM, which was studied for effective topical application in dermatological diseases [56]. Notably, LEO 29102 is a novel soft-drug that is designed by introducing 2ʹ-alkoxy substituents and exchanging the amide group into a keto linker on the basis of piclamilast (36, Figure 9). LEO 29102 has been found to show good efficacy in the clinical treatment of patients with atopic dermatitis, while no leading to emesis and other side effects. Moreover, LEO 29102 has conducted a phase II clinical trial for the treatment of psoriasis though further progress has not been reported [80]. Collectively, LEO 29102 puts forward the concept of soft drug, aiming to eliminate the systemic side effects caused by PDE4 inhibitors.