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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.
More than a random association between chronic obstructive pulmonary disease and psoriatic arthritis: shared pathogenic features and implications for treatment
Published in Expert Review of Clinical Immunology, 2022
Luca Quartuccio, Marco Sebastiani, Francesca Romana Spinelli, Fabiano Di Marco, Rosario Peluso, Salvatore D’Angelo, Alberto Cauli, Maurizio Rossini, Fabiola Atzeni
The development of selective PDE-4 inhibitors in the treatment of COPD offers both anti‐inflammatory and broncho-dilatory effects, with fewer of the adverse effects encountered with non‐selective inhibitors. Additionally, PDE-4 inhibitors may be easier to use because they provide less pharmacokinetic variability and lower potential for drug interactions, compared with non‐selective inhibitors. PDE-4 inhibitors, in particular Roflumilast, have been largely studied to treat chronic airway diseases including COPD and asthma. Most evidence has been gathered for Roflumilast at a dose of 500 μg daily. A recent meta-analysis found 43 RCTs for Roflumilast (28 trials with 18,046 participants), Cilomilast (14 trials with 6457 participants), or Tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer, and including people across international study centers with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV) [38]. Based on the risk benefit ratio, the authors of this review provided cautious support for the use of PDE-4 inhibitors in COPD, placing them as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management. Trials with longer follow-up are needed to show whether PDE-4 inhibitors can modify FEV₁ decline, hospitalization, or mortality in COPD [38].
DRM02, a novel phosphodiesterase-4 inhibitor with cutaneous anti-inflammatory activity
Published in Tissue Barriers, 2020
David W.C. Hunt, Iordanka A. Ivanova, Lina Dagnino
Within the superfamily of PDE enzymes, the type-4 (PDE4) family is a major player in the regulation of cellular pro-inflammatory responses. PDE4 exerts key roles in inflammatory disorders, and is relatively abundant in myeloid and lymphoid cells.6,7 Several PDE4 isoforms are also expressed in epidermal keratinocytes.8 PDE4 catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), thereby inactivating this second messenger.6 Inhibition of PDE4 increases cAMP levels, which, in turn, interferes with pro-inflammatory processes in epidermal cells in vitro, and in preclinical in vivo models of cutaneous inflammatory disorders.9–11 Several PDE4 inhibitors, including apremilast and cilomilast, are now clinically used to decrease the expression of key pro-inflammatory cytokines, including tumor necrosis factor (TNF) α, interleukin (IL)-6, IL-17 and IL-23.7,9,11,12 However, there remains an ongoing need for the introduction of effective novel anti-inflammatory drugs, as some clinically approved PDE4 inhibitors can also exert dose-limiting systemic toxicities.13
Human total clearance values and volumes of distribution of typical human cytochrome P450 2C9/19 substrates predicted by single-species allometric scaling using pharmacokinetic data sets from common marmosets genotyped for P450 2C19
Published in Xenobiotica, 2021
Shogo Matsumoto, Shotaro Uehara, Hidetaka Kamimura, Hiroshi Ikeda, Satoshi Maeda, Machiko Hattori, Megumi Nishiwaki, Kazuhiko Kato, Hiroshi Yamazaki
The model compounds used in the present study are listed in Table 1. Acetaminophen, diclofenac, glyburide, ibuprofen, itraconazole, ketanserin, ketoprofen, lamotrigine, moxifloxacin hydrochloride monohydrate, nicardipine hydrochloride, phenytoin, repaglinide, telmisartan, tolbutamide, and verapamil hydrochloride were purchased from Tokyo Chemical Industry (Tokyo, Japan). Antipyrine, clonazepam, midazolam, and probenecid were from FUJIFILM Wako (Osaka, Japan). Dapsone, pefloxacin mesylate, S-warfarin, and zaleplon were purchased from Toronto Research (Toronto, Canada), MedChem Express (South Brunswick Township, NJ), Cayman Chemical (Pittsfield Charter Township, MI) and Key Organics (London, UK), respectively. Cilomilast was synthesised inhouse according to the method of Christensen et al. (1998) (1H NMR (400 MHz, CDCl3) δ [ppm] 1.58–1.67 (m, 2H), 1.75–2.10 (m, 10H), 2.19–2.31 (m, 4H), 2.37–2.46 (m, 1H), 3.85 (s, 3H), 4.78–4.84 (m, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H)). These chemicals were chosen because they are mainly eliminated by hepatic metabolism; the exceptions are moxifloxacin and ketoprofen, which have renal excretion ratios of 21.9% and 30.0%, respectively, in humans (Varma et al.2010). Human CYP2C isoforms are fully or partly involved in the metabolism of about half the tested compounds. Other P450 or non-P450 enzymes, such as aldehyde oxidase, ketone reductase, UGT, sulphotransferase, and N-acetyltransferase, are responsible for the metabolic elimination of the other compounds in humans (Table 1). The reagents and solvents used were of analytical and HPLC grade.