Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
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].
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.
Experimental and investigational phosphodiesterase inhibitors in development for asthma
Published in Expert Opinion on Investigational Drugs, 2019
Polyxeni Ntontsi, Aggeliki Detta, Petros Bakakos, Stelios Loukides, Georgios Hillas
Cilomilast is a second generation PDE inhibitor, under evaluation in phase II and III clinical trials with impressive results mostly in COPD and less in asthma by improving lung function with a satisfactory safety profile [36,50]. YM976 inhibits antigen-induced bronchoconstriction, airway oedema, airway eosinophil accumulation and AHR in guinea pigs like rolipram but with a better safety profile and less adverse events [51]. The most common adverse events of PDE4 inhibitors were gastrointestinal disorders, dizziness and headaches [42,46,49].
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