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A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium.
Supuran, CT, Capasso, C
International journal of molecular sciences. 2021;(9)
Abstract
Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms' metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3-) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3- and protons. Opportunistic and pathogenic fungi can sense the environmental CO2 levels, which influence their virulence or environmental subsistence traits. The fungal CO2-sensing is directly stimulated by HCO3- produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO2/HCO3-/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel "pathogen protein" target of many opportunistic, pathogenic fungi.
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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study.
Wada, T, Inagaki, M, Yoshinari, T, Terata, R, Totsuka, N, Gotou, M, Hashimoto, G
Clinical and experimental nephrology. 2021;(2):120-130
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BACKGROUND We investigated the efficacy and safety of apararenone (MT-3995), a non-steroidal compound with mineralocorticoid receptor agonist activity, in patients with stage 2 diabetic nephropathy (DN). METHODS The study had two parts: a dose-response, parallel-group, randomized, double-blind, placebo-controlled, multicenter, phase 2, 24-week study and an open-label, uncontrolled, 28-week extension study. Primary and secondary endpoints were the 24-week percent change from baseline in urine albumin to creatine ratio (UACR) and 24- and 52-week UACR remission rates. Safety parameters were changes from baseline in estimated glomerular filtration rate (eGFR) and serum potassium at 24 and 52 weeks, and incidences of adverse events (AEs) and adverse drug reactions (ADRs). RESULTS In the dose-response period, 73 patients received placebo and 73, 74, and 73 received apararenone 2.5 mg, 5 mg, and 10 mg, respectively. As a percentage of baseline, mean UACR decreased to 62.9%, 50.8%, and 46.5% in the 2.5 mg, 5 mg, and 10 mg apararenone groups, respectively, at week 24 (placebo: 113.7% at week 24; all P < 0.001 vs placebo). UACR remission rates at week 24 were 0.0%, 7.8%, 29.0%, and 28.1% in the placebo and apararenone 2.5 mg, 5 mg, and 10 mg groups, respectively. eGFR tended to decrease and serum potassium tended to increase, but these events were not clinically significant. AE incidence increased with dose while ADR incidence did not. CONCLUSION The UACR-lowering effect of apararenone administered once daily for 24 weeks in patients with stage 2 DN was confirmed, and the 52-week administration was safe and tolerable. CLINICAL TRIAL REGISTRATION NCT02517320 (dose-response study) and NCT02676401 (extension study).
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Efficacy of vonoprazan against bleeding from endoscopic submucosal dissection-induced gastric ulcers under antithrombotic medication: A cross-design synthesis of randomized and observational studies.
Hidaka, Y, Imai, T, Inaba, T, Kagawa, T, Omae, K, Tanaka, S
PloS one. 2021;(12):e0261703
Abstract
Vonoprazan, a potassium-competitive acid blocker, is expected to be superior to proton pump inhibitors (PPIs) in preventing post-endoscopic submucosal dissection (ESD)-induced gastric bleeding. However, the results of randomized controlled trials (RCTs) and observational studies on the efficacy of vonoprazan have been inconsistent. This study aimed to evaluate the effectiveness of vonoprazan in antithrombotic drug users, a population that has been excluded from RCTs. Treatment effects were assessed using cross-design synthesis, which can be adjusted for differences in study design and patient characteristics. We used data from an RCT in Japan (70 patients in the vonoprazan group and 69 in the PPI group) and an observational study (408 patients in the vonoprazan group and 870 in the PPI group). After matching, among the antithrombotic drug users in the observational study, post-ESD bleeding was noted in 8 out of 86 patients in the vonoprazan group and 18 out of 86 patients in the PPI group. After pooling the data from the RCT and observational study, the risk difference for antithrombotic drug users was -14.6% (95% CI: -22.0 to -7.2). CDS analysis suggested that vonoprazan is more effective than PPIs in preventing post-ESD bleeding among patients administered antithrombotic medications.
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Ramatroban-Based Analogues Containing Fluorine Group as Potential 18F-Labeled Positron Emission Tomography (PET) G-Protein Coupled Receptor 44 (GPR44) Tracers.
Huang, LA, Huang, KX, Tu, J, Kandeel, F, Li, J
Molecules (Basel, Switzerland). 2021;(5)
Abstract
Diabetes remains one of the fastest growing chronic diseases and is a leading source of morbidity and accelerated mortality in the world. Loss of beta cell mass (BCM) and decreased sensitivity to insulin underlie diabetes pathogenesis. Yet, the ability to safely and directly assess BCM in individuals with diabetes does not exist. Measures such as blood glucose provide only a crude indirect picture of beta cell health. PET imaging could, in theory, allow for safe, direct, and precise characterization of BCM. However, identification of beta cell-specific radiolabeled tracers remains elusive. G-protein coupled receptor 44 (GPR44) is a transmembrane protein that was characterized in 2012 as highly beta cell-specific within the insulin-positive islets of Langerhans. Accordingly, radiolabeling of existing GPR44 antagonists could be a viable method to accelerate PET tracer development. The present study aims to evaluate and summarize published analogues of the GPR44 antagonist ramatroban to develop 18F-labeled PET tracers for BCM analysis. The 77 corresponding ramatroban analogues containing a fluorine nuclide were characterized for properties including binding affinity, selectivity, and pharmacokinetic and metabolic profile, and 32 compounds with favorable properties were identified. This review illustrates the potential of GPR44 analogues for the development of PET tracers.
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Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.
Kim, ST, Smith, SA, Mortimer, P, Loembé, AB, Cho, H, Kim, KM, Smith, C, Willis, S, Irurzun-Arana, I, Berges, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(17):4700-4709
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PURPOSE Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. PATIENTS AND METHODS Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. RESULTS The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9). CONCLUSIONS Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.See related commentary by Ashworth, p. 4667.
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Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2).
Chey, WD, Lembo, AJ, Yang, Y, Rosenbaum, DP
The American journal of gastroenterology. 2021;(6):1294-1303
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INTRODUCTION Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). METHODS In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder). RESULTS Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively. DISCUSSION Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).
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Combination of Intravitreal Bevacizumab and Topical Dorzolamide versus Intravitreal Bevacizumab Alone for Diabetic Macular Edema: A Randomized Contralateral Clinical Trial.
Fazel, F, Nikpour, H, Pourazizi, M
BioMed research international. 2020;:6794391
Abstract
PURPOSE To evaluate the efficacy of three intravitreal bevacizumab (IVB) injections versus the same combined with 2% of topical dorzolamide in the treatment of diabetic macular edema (DME). METHODS In this randomized double-masked clinical trial, 32 eyes of 16 treatment-naive patients with bilateral DME were enrolled. The eyes were randomly assigned to receive three monthly injections of IVB (1.25 mg) plus topical dorzolamide 2% twice daily or IVB (1.25 mg) plus topical artificial tear twice daily. Best-corrected visual acuity (BCVA) was the primary outcome of the study followed by the central macular thickness (CMT) and central macular volume (CMV) as the secondary outcomes. RESULTS Mean BCVA changes were insignificant in both groups. It changed from 0.21 ± 0.08 logMAR at baseline to 0.23 ± 0.09 (P=0.24) in the combination group and from 0.18 ± 0.09 logMAR to 0.21 ± 0.09 (P=0.11) in the IVB alone group, at 3 months, respectively. Changes in mean CMT and CMV were significant in both groups. However, the difference between the groups was not significant at all the visits. In the study, no major ocular complication or systemic side effects were noted regarding IVB or topical dorzolamide. CONCLUSION This randomized contralateral clinical trial demonstrated that adjuvant topical dorzolamide with IVB injection had no additional effects on IVB in the treatment of DME over a three-month course. This trial is registered with the Iranian Registry of Clinical Trials under the registration code IRCT20131229015975N5.
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Trifluoromethanesulfonamide vs. Non-Fluorinated Sulfonamides in Oxidative Sulfamidation of the C=C Bond: An In Silico Study.
Kuzmin, AV, Moskalik, MY, Shainyan, BA
Molecules (Basel, Switzerland). 2020;(21)
Abstract
A theoretical analysis of the reaction of oxidative sulfamidation of several alkenes was performed in order to explain the various experimental observations and different reactivity of triflamide and non-fluorinated sulfonamides. Transformations occurring in the system alkene-sulfonamide in the presence of oxidative system (ButOCl + NaI) were analyzed at the MP2/DGDZVP//B3LYP/DGDZVP level of theory using the IEF-PCM method for taking into account the solvent acetonitrile (MeCN) effect. As the model substrates, styrene, trimethyl(vinyl)silane, dimethyl(divinyl)silane and diphenyl(divinyl)silane were chosen and mesylamide, triflamide, tosylamide and p-nosylamide were taken as the reagents. ButOI generated from ButOCl and NaI reacts with sulfonamides to give N-iodinated sulfonamides RSO2NHI and RSO2NI2 as active intermediates, the iodinating activity of the latter being notably higher. The analysis allowed to answer such challenging questions as different reactivity of nonfluorinated sulfonamides leading to aziridination and of triflamide resulting in the formation the main products of bis-triflamidation, or different regioselectivity of halogenation of styrene and trimethyl(vinyl)silane caused by a linear intermediate iodonium cation in the former case and a cyclic one in the latter.
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Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Nav 1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects.
Siebenga, P, van Amerongen, G, Hay, JL, McDonnell, A, Gorman, D, Butt, R, Groeneveld, GJ
Clinical and translational science. 2020;(2):318-324
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Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Nav 1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons. The aim was to demonstrate analgesic properties of a potent selective Nav 1.7 sodium channel blocker, PF-05089771, alone and concomitantly with pregabalin in healthy subjects using a battery of human evoked pain models. This was a double-blind, double-dummy, randomized, placebo-controlled, five-period cross-over study with PF-05089771 alone and PF-05089771 concomitantly with pregabalin as treatment arms with pregabalin, ibuprofen, and placebo as control arms (NCT02349607). A battery of human evoked pain models was used to investigate analgesic properties of PF-05089771. Twenty-five subjects were enrolled in the study of which 23 subjects completed all five periods. PF-05089771 alone did not differ from placebo on the primary pain end points. The same holds when comparing PF-05089771 concomitantly with pregabalin and pregabalin alone. Pregabalin showed significant effects relative to placebo on thermal pain on the normal skin and UVB skin (least squares means with 90% confidence interval: 0.63 (0.32-0.93) and 0.53 (0.11-0.96)), pressure stimulation (1.10 (1.04-1.18)), and cold pressor (1.22 (1.14-1.32)). Ibuprofen demonstrated significant effects on thermal pain UVB skin (1.26 (0.82-1.70)) and pressure stimulation assessment (1.08 (1.01-1.15)), consistent with historical results. This study did not demonstrate analgesic properties of PF-05089771 alone or concomitantly with pregabalin in a battery of pain models.
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EMT-inducing transcription factor ZEB1-associated resistance to the BCL-2/BCL-XL inhibitor is overcome by BIM upregulation in ovarian clear cell carcinoma cells.
Inoue-Yamauchi, A, Oda, H
Biochemical and biophysical research communications. 2020;(3):612-617
Abstract
Ovarian clear cell carcinoma (OCCC) is an aggressive subtype of epithelial ovarian cancer, which generally exhibits chemoresistance. Effective therapy for OCCC is currently unavailable, requiring the development of new therapeutic strategies. ABT-263 (navitoclax), an inhibitor of the anti-apoptotic BCL-2/BCL-XL, has a potent ability of inducing death in cancer cells; however, the therapeutic effect of ABT-263 in OCCC remains unclear. Epithelial cells undergo epithelial-mesenchymal transition (EMT) to acquire a mesenchymal phenotype, which is known to contribute to the development of resistance against therapeutic agents. In this study, we revealed that the sensitivity of OCCC cells to ABT-263 was associated with the epithelial/mesenchymal status of the cells. While the OCCC cells with an epithelial phenotype were ABT-263-sensitive, those with a mesenchymal phenotype were ABT-263-resistant, which was accompanied by an insufficient expression of the pro-apoptotic BH3 protein BIM. Mechanistically, the EMT-inducing transcription factor, ZEB1 down-regulated BIM transcription by binding to BIM promoter, resulting in resistance to ABT-263. It is noteworthy that ZEB1-associated ABT-263 resistance was overcome by an HDAC inhibitor, FK228 (romidepsin), through the up-regulation of BIM. In summary, our study provides evidence for a mechanism for ABT-263 resistance in OCCC cells as well as a potential therapeutic strategy to overcome it.