Voriconazole

Voriconazole (Vfend™) is a 2nd-generation triazole antifungal medication, and etravirine (Intelence™) is a nonnucleoside reverse transcriptase inhibitor for the handling of HIV.

From: Progress in Heterocyclic Chemistry , 2012

Methods of Therapeutic Drug Monitoring Including Pharmacogenetics

Andreas H. Groll , Silke Gastine , in Handbook of Belittling Separations, 2020

9.5.5 Clinical Indications

Voriconazole has demonstrated first-class clinical efficacy in phase Ii and Three clinical trials in patients with oropharyngeal candidiasis and esophageal candidiasis [28,289] and is canonical in the United States for handling of esophageal candidiasis [305]. A randomized clinical trial comparing voriconazole to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in non-neutropenic patients showed similar response rates at end-of-treatment and similar survival rates at 3 months [306]. Based on this trial and data from noncomparative studies, voriconazole is approved in both the Us and Europe for handling of candidemia in non-neutropenic patients and other deep tissue Candida infections [305,307].

A historical, multinational, randomized phase Iii clinical trial of voriconazole versus amphotericin B deoxycholate followed past other licensed antifungal agents for treatment of invasive aspergillosis revealed superior outcomes in voriconazole-treated patients in terms of treatment response and overall survival [290] and established voriconazole as standard of treat main handling of invasive aspergillosis [308]. At calendar week 12, successful outcomes were noted in 52.8% and 31.6% of patients with 70.8% overall survival in the voriconazole accomplice and 57.9% in the comparator arm, respectively. Voriconazole-treated patients had significantly fewer severe drug-related adverse events [290]. A subsequent randomized double-bullheaded clinical trial comparison open-label voriconazole plus blinded anidulafungin or blinded placebo showed a statistical trend (P  =   .07) favoring the combination therapy with respect to overall survival at 6   weeks, the primary endpoint of the study [309]. In a post hoc analysis of patients diagnosed on the basis of positive galactomannan antigen detection, overall survival at 6   weeks was significantly higher for the combination. While in that location is an ongoing argue about the clinical implications of this study, regulatory approval of the combination for invasive aspergillosis has failed [305,307].

Based on favorable responses in salvage studies in patients with infections refractory or intolerant to available treatment [273,310], voriconazole also is approved and recommended for treatment of patients with scedosporiosis and fusariosis [305,307,311]. Several reports also suggest the potential usefulness of voriconazole for treatment of infections past unusual hyaline and dematiaceous fungi [310], besides equally for treatment of cerebral mold infections [312].

Voriconazole also has been investigated as master antifungal prophylaxis [313,314]. In a multicenter, randomized, double-blind trial of voriconazole versus fluconazole in 600 allogeneic HSCT patients, no deviation was recorded in the cumulative rates of presumptive, probable, or proven invasive fungal infections at half-dozen months; still, a trend was noted toward fewer infections past Aspergillus (9% vs. 17%, P  =   .09) [314]. A second written report compared voriconazole to itraconazole in 489 allogeneic HSCT recipients. Efficacy was assessed past a blended endpoint, including survival at 180 days after transplantation, no likely or proven breakthrough infections and no discontinuation of the study drug for more than fourteen days during the first scheduled 100 days. Using this endpoint, voriconazole was superior to itraconazole, with a 49.one versus 34.five% success rate (P  =   .0004) [313]. On the basis of these data, voriconazole is canonical in Europe, but not the United States for antifungal prophylaxis in allogeneic HSCT recipients [305,307].

Read total chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780444640666000095

Diagnosing and Improving Pharmacokinetic Operation

Li Di , Edward H. Kerns , in Drug-Similar Backdrop (2d Edition), 2016

38.three.2 Pharmacokinetics of Triazole Antifungal Voriconazole

Voriconazole ( Figure 38.3) has good solubility and first-class oral absorption. In humans, less than vii% voriconazole is eliminated through feces. It is mostly eliminated by hepatic clearance. Oral bioavailability of the drug is greater than 70% in humans. Voriconazole produced an unusual nonlinear PK profile (Effigy 38.4) following the PO or Iv administration in rat, which has been termed a "hockey-stick" profile [4]. The PK characteristics are gender dependent. The analog chemical compound in Figure 38.v does non have the nonlinear PK characteristics, due to the depression log D (0.v), and is eliminated mostly by kidney. Table 38.3 lists the gender-dependent PK parameters of voriconazole. The oral AUC (dose normalized) at 30   mg/kg was higher than IV AUC at 10   mg/kg, resulting in greater than 100% oral bioavailability (%F  =   159%) in male person rat.

Figure 38.3. Structure and physicochemical properties of triazole antifungal voriconazole.

Effigy 38.iv. Nonlinear PK of voriconazole in rat [4].

 (Used with permission from Roffey, S.J., Cole, S., Comby, P., Gibson, D., Jezequel, S.G., Nedderman, A.N.R., Smith, D.A., Walker, D.K., Wood, N. (2003). The disposition of voriconazole in mouse, rat, rabbit, guinea pig, canis familiaris, and human. Drug Metab. Dispos., 31, 731–741.) Copyright © 2003 American Society for Pharmacology and Experimental Therapeutics.

Figure 38.5. Effects of log D on clearance and PK.

Table 38.3. Voriconazole: PK Information Estimation in Rat [four]

Sexual activity Male Female
Plasma protein binding (%) 66 66
IV
Dose (mg/kg) 10 10
Single dose AUCt (ug   h/mL) 18.half dozen 81.half-dozen Gender dependent
Multiple dose AUCt (ug   h/mL) vi.7 13.9 <   S.D. CYP450 auto-induction
Oral
Dose (mg/kg) 30 30
Unmarried dose C max (ug/mL) 9.v 16.7 Gender dependent
Single dose T max (h) 6 one Gender dependent
Single dose AUCt (ug   h/mL) 90 215.half-dozen >   Four, capacity-limited elimination
Multiple dose AUCt (ug   h/mL) 32.3 57.4 <   S.D. CYP450 machine-induction
Apparent bioavailability F (%) 159 88 Capacity-limited elimin. Practiced assimilation

Used with permission from Southward.J. Roffey, South. Cole, P. Comby, D. Gibson, South.G. Jezequel, A.N.R. Nedderman, D.A. Smith, D.K. Walker, N. Wood, The disposition of voriconazole in mouse, rat, rabbit, republic of guinea pig, dog and homo, Drug Metab. Dispos. 31 (2003) 731–741.

Copyright © 2003 American Society for Pharmacology and Experimental Therapeutics.

This was diagnosed equally capacity-limited emptying, due to saturation of metabolizing enzymes. The loftier assimilation of the drug produced high exposure of the compound in systemic circulation.

Another issue was that during multiple dosing by IV or oral assistants, the AUC was lower than that during single dosing. This was diagnosed every bit being due to autoinduction of CYP450 metabolic enzyme by voriconazole. Consequent with this diagnosis, there was an increase in liver weight and CYP450 enzyme activity with the multiple doses (Tabular array 38.iv). As animals were exposed to voriconazole, more CYP450 enzyme was induced, which metabolized voriconazole at a higher rate and the drug was eliminated faster. Hence, multiple dosing generated lower AUC than single dosing.

Tabular array 38.4. Voriconazole: Autoinduction of CYP450s [4]

Dose (mg/kg) Hepatic Microsomal Cytochrome P450 (nmol P450/mg protein) Relative Liver Weight Voriconazole C max (ug/mL)
Male Female Male person Female Male Female
Control 0.88 0.51 three.71 three.vii None None
3 0.85 0.65 three.86 iv.04 0.61 1.32
ten 1.21 0.68 4.17 4.26 three.64 6.xiv
30 i.77 0.79 4.38 5.04 9.69 fourteen.6
80 2.08 0.92 5.57 6.26 28.iv 30.4

Used with permission from S.J. Roffey, Due south. Cole, P. Comby, D. Gibson, S.1000. Jezequel, A.N.R. Nedderman, D.A. Smith, D.Yard. Walker, N. Wood, The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog and human being, Drug Metab. Dispos. 31 (2003) 731–741.

Copyright © 2003 American Society for Pharmacology and Experimental Therapeutics.

Read full affiliate

URL:

https://www.sciencedirect.com/science/article/pii/B9780128010761000381

Advances in Clinical Mass Spectrometry

D. French , in Advances in Clinical Chemistry, 2017

five.1.3 Antifungals

Azole antifungal drugs such equally voriconazole, posaconazole, ketoconazole, fluconazole, and itraconazole are used in patients primarily to treat invasive aspergillosis and/or candidiasis infections [52,53]. Since these drugs exhibit large intra- and interindividual variability due to metabolism past cytochrome P450 enzymes, dosing when fasting vs later on a meal, and drug–drug interactions, TDM is recommended when they are prescribed [52]. A third political party immunoassay is available for voriconazole measurement that can be implemented on major vendor's chemistry analyzers; even so, information technology is not yet FDA-approved meaning the laboratory would have to do a full analytical validation should they wish to implement this assay [ane,54]. An advantage of using this immunoassay is that since information technology is performed on random admission chemistry analyzers, testing can exist performed 24/7 which would improve the turn-around time over batched MS methods. The lack of available immunoassays for antifungal drugs compels clinical laboratories to either send samples for assay to reference laboratories or to develop their own methods using high-performance liquid chromatography (HPLC), or LC-MS, or LC-MS/MS [55–59].

The majority of published LC-MS/MS methods use serum or plasma for analysis of one or more antifungals, and metabolites, and the required sample volume ranges from 5 to 200   μL, which is reasonable even for pediatric patients [58–62]. A disadvantage of using MS-based methods over immunoassay methods is the requirement for sample training. For the antifungal drugs, sample training is by and large kept to a minimum with a number of studies utilizing PPT [58,62]. Nonetheless, simplifying the sample preparation in this way does not eliminate all of the matrix components that can cause suppression of the MS signal, for example, phospholipids, which tin add unwanted variation to the method [xv]. Some authors accept employed LLE, SLE, or online extraction after PPT, to help eliminate these matrix components [59,63,64]; nonetheless, this increases the turn-around time of the assay.

A published LC-MS method used 50   μL of plasma spotted on a dry sample spot device for analysis of voriconazole, posaconazole, and itraconazole and plant it stable for up to two weeks [57]. This type of sample drove device would obviate the need for, and cost of temperature-controlled sample transportation for sending samples to reference laboratories for analysis by MS methods. In some other study, dried blood spot analysis of voriconazole, fluconazole, and posaconazole was plant to be suitable for TDM of these triazoles by LC-MS/MS [65]. Patients that are prescribed antifungal drugs are most likely immunocompromised and may be critically ill. Therefore, a reduction in the blood volume taken from the patient would be an obvious reward of dried claret spot sampling, especially in pediatric patients. A farther advantage is the perceived reduction in hurting experienced past patients in dried blood spot sampling vs venipuncture; although critically ill, patients in a hospital would likely have a central line for claret sampling (pain perception was recorded past patient questionnaire) [65]. If the patients are released from infirmary while all the same prescribed these drugs, DBS sampling would permit TDM to go along by the patient being able to self-administer a finger-stick, collect the blood spot on the card, and ship the DBS bill of fare to the laboratory.

Since it is possible to measure out all of these antifungal drugs in one MS method, the workflow is not as challenging for the laboratory to implement as it would be if an analysis had to be developed for each drug independently, although a complete analytical validation would be necessary for each drug inside the method. Further, isavuconazole is a new azole drug that was approved for use in the handling of invasive aspergillosis and mucormycosis in 2015. Currently only one reference laboratory offers testing for this drug, limiting the availability for clinical laboratories and increasing the plough-around fourth dimension over offering this assay in-business firm. However, this drug could potentially be added into a current azole MS method and analytically validated, allowing the workflow to remain similar which is a great advantage of this technology. The only additional work for the laboratory would be to industry new lots of calibrators and quality command material containing isavuconazole, or buy them from a vendor.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/commodity/pii/S0065242316300828

Methods of Therapeutic Drug Monitoring Including Pharmacogenetics

Roger Jelliffe , ... David Bayard , in Handbook of Analytical Separations, 2020

vii.iv.7 Another assay example—voriconazole

At Children'southward Hospital of Los Angeles, TDM of voriconazole employs an LCMS-MS assay [xv,16], a NP population PK model of voriconazole [17], and the USC Bestdose clinical software [3]. The assay was developed utilizing positive mode to quantify voriconazole (thou/z 350.1/281.20) using D3-voriconazole (m/z 353.ane/284.ii) as an internal standard.

The AEP of this analysis was analyzed using 7 samples, each measured in quintuplicate. The samples were a blank, 0.02   ug/mL, 0.5   ug/mL, 5.0, 12.5, xxx, and forty   ug/mL. These seven samples gave mean values   ±   SDs of 0.00592   ±   0.000239, 0.177   ±   0.00118, 0.487   ±   0.0121, 5.364   ±   0.8385, 13,94   ±   0.1342, 29.58   ±   0.642, and 38.54   ±   0.381   ug/mL respectively.

When that data were analyzed with the makeErrorPoly function in Pmetrics [x] the post-obit AEPs were found, as shown in Fig. vii.half dozen.

Figure 7.6

Figure seven.half-dozen. Plot of voriconazole measured concentrations (horizontal) and assay standard deviation (vertical). The solid line represents the graph of the starting time-degree polynomial, the dashed line the second-caste polynomial, and the dotted line the third-caste polynomial.

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780444640666000071

Other Five-membered Rings with Three or more Heteroatoms, and their Fused Carbocyclic Derivatives

Vladimir A. Ostrovskii , ... Rostislav Eastward. Trifonov , in Comprehensive Heterocyclic Chemical science IV, 2022

half-dozen.07.6.ane.iii Antifungal activity

Compounds having a pronounced antifungal upshot are known amongst tetrazole derivatives. Thus, tetrazole-containing analogs of voriconazole and itraconazole showed antifungal activity. 182 Tetrazole 173 (VT-1161) with a M d <   0.039   μM 182 turned out to be the virtually effective and highly selective compound confronting C. albicans-CYP51 and compound 174 (VT-1598) was even more effective against A. fumigatus-CYP51 (Thousand d 13   nM). 183 Yang et al. synthesized a large series of related tetrazole containing compounds (175) which prove a good activity against Candida spp and Cryptococcus neoformans with two representative compounds being more active against Microsporum gypseum in comparison with compound 173 (VT-1161). 184

Kathiravan et al. have synthesized and investigated antifungal activity of 16 phenyl (iiH-tetrazole) methylamine derivatives and found that tetrazole 176 was active confronting C. albicans (500   μg   mL−   1) and Aspergillus niger (750   μg   mL−   i). 185

A series of 1,v- and two,5-dissubtituted tetrazoles containing a 2-chloroquinoline substituent was synthesized. Tetrazoles 177 and 178 demonstrated very loftier in vitro activity against A. fumigatus and C. Albicans. 186

Tetrazole-containing aminopyrimidine derivatives, 4-(four-(1H-tetrazol-1-yl)aryl)-6-phenylpyrimidin-ii-amines 179, demonstrated a high antifungal action in vitro comparable to the standard fluconazole (MIC 0.sixteen–25   mg   mL−   1), against C. albicans, S. cerevisiae, A. niger, and A. fumigatus. 187 The same authors showed that a tetrazole substituted chalcone 180 significantly exceeded the action fluconazole against the aforementioned fungal strains (Fig. 21). 188

Fig. 21

Fig. 21. Tetrazoles with antifungal issue.

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128186558001311

Therapeutic Areas II: Cancer, Infectious Diseases, Inflammation & Immunology and Dermatology

P. Dorr , in Comprehensive Medicinal Chemistry Ii, 2007

vii.14.5.3.three New antifungal drugs

The dominance of fluconazole and amphotericin B in the treatment of serious fungal infections has been recently challenged by newer drugs. Indeed, the new antifungal agents voriconazole, caspofungin, and micafungin are quickly establishing a place in the clinician'southward antifungal armory, and are now available for the treatment of systemic fungal infections. Voriconazole is an extended-spectrum triazole that is fungicidal for many filamentous fungi, including Aspergillus, Scedosporium, Fusarium, and Paecilomyces, and is agile against all species of Candida. 97,98 Clinical trials have shown that handling with voriconazole cleared Candida from the blood as apace equally amphotericin B, with a lower incidence of treatment-related adverse events. Subsequently, it was approved for the first-line handling of invasive aspergillosis and as salve therapy for fungal infections caused by the pathogens Scedosporium apiospermum and Fusarium species. More than recently, voriconazole was approved for use in treating esophageal candidiasis. 98 This is a reflection of its impressive activeness against filamentous fungi, in particular Aspergillus, where it exerts fungicidal action, equally seen in a variety of in vivo and in vitro models. 99,100 Voriconazole is given either by the oral or the intravenous route. Different fluconazole, voriconazole is not renally cleared in light of its higher lipophilicity. Clearance is cytochrome P450-mediated. The effects of voriconazole on cytochrome P450-mediated metabolism means that clinicians must be aware of drug–drug interactions. The clinical pharmacokinetics of voriconazole have been described in item past Purkins et al. 101 Voriconazole represents the almost advanced and widely used tertiary-generation azole antifungal, with posaconazole and ravuconazole (see 7.xv Major Antifungal Drugs) likewise showing promising broad-spectrum activity.

The most obvious rational starting point for a drug discovery program would be to target the cell wall of fungal pathogens, in light of its essentiality for pathogen viability, and total absence in host cells, despite the commonality of their eukaryotic origin. This approach has been aggressively targeted past drug researchers, as seen past the massive success demonstrated with the penicillin and cephalosporin series of antibacterial antibiotics. 102 Despite the complex nature of fungal cell walls (a highly structured complex of mannan, β-glucan, and n-acetyl glucosamine (chitin)-based polymers 103 ) and their biosynthesis, highlighting a host of target areas for antifungal drug discovery, information technology is arguably disappointing that relatively footling success has been fabricated (with one exception) in terms of novel drug series. Numerous attempts and screens to find inhibitors of chitin synthases have been undertaken, and inhibitors such equally the natural products nikkomycin and poloxin accept been discovered. 104 Still, these have not led to clinical candidates, and other more amenable inhibitors to a drug discovery programme have not been forthcoming. Similarly, the pradamicins, which bind to mannans in the prison cell wall, take proven to be of express value as an antifungal drug lead. 102 These are far from existence antifungal drugs due to inherent limitations in say-so and unfavorable physicochemical properties that limit their systemic bioavailability. Despite the substantial effort of medicinal chemists and biotransformation scientists to improve the pradamicins, little of therapeutic utilize has emerged from these starting points. One notable exception in the search for new drugs that target the jail cell wall of fungi is the discovery, evolution, and successful commercialization of the echinocandin and pneumocandin drugs (reviewed by Denning, 105 and discussed in item in 7.15 Major Antifungal Drugs). These agents inhibit the glucan synthase enzyme responsible for the β-glucan polymer, a major elective of the cell wall. Clinical trials have highlighted amphotericin-like efficacy, in empirical-based therapy, with superior tolerance. 86 The about successful of these to date is caspofungin (Cancidas), which is a semisynthetic analog of a pneumocandin lead. 106 Caspofungin has subsequently progressed through clinical development, and met with considerable success for the empirical therapy of fungal infections in febrile neutropenic patients. Approving was based on results from the largest prospective antifungal empirical therapy trial published to date in neutropenic patients, where caspofungin was as effective equally amphotericin (Ambisome) but with fewer side effects. 86 This represents a breakthrough in supplanting the gilt standard amphotericin B with a safer amanuensis for many deep-seated life-threatening infections. Caspofungin is also active against aspergillosis, 107 and has been used successfully in combination with voriconazole for this life-threatening mycoses. 108 Caspofungin is currently the most widely used glucan synthase inhibitor for the treatment of serious fungal infections. Micafungin (Mycamine), has a very similar profile, and has been approved for prophylaxis against Candida infection as well as esophageal candidasis. Other agents in this class are also showing slap-up promise. Clinical studies with anidulafungin (Eraxis) accept been encouraging, 109 where recent Phase 3 studies showed information technology to exist superior to fluconazole against invasive candidiasis, yet with a similar rubber profile.

Yet, a limitation of caspofungin, and the candin class of antifungal drugs in general, is the lack of an oral route of administration. Efforts by medicinal chemists and drug discoverers are ongoing to observe new modest molecule templates for the inhibition of glucan synthase (eastward.g., come across Onishi 110 ), although this has currently met with limited success.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/article/pii/B008045044X002157

5-membered Rings: Triazoles, Oxadiazoles, Thiadiazoles and their Fused Carbocyclic Derivatives

A.D.Thou. Curtis , N. Jennings , in Comprehensive Heterocyclic Chemistry III, 2008

v.02.12.1 Pharmaceuticals

A wide variety of antifungal agents have been further adult that contain a 1,2,iv-triazole moiety; fluconazole 231 is probably the most widely recognized with voriconazole 232 , ketoconazole 233 , itraconazole 234 , and posaconazole 235 being developed subsequently <2002MI550, 2003MI272, 2005MI1553, 2005MI91, 2005MI1215, 2005JIB1558, 2005MI775, 2006MI483, 2006MI579>.

The link between estrogen levels and the evolution of breast cancer is well established and several drugs have been developed to regulate estrogen synthesis past inhibiting the enzyme aromatase; aromatase catalyzes the final footstep in steroid biosynthesis and is thus an excellent target. Several nonsteroidal aromatase inhibitors take been adult, including letrozole 236 and anastrozole 237 <2002MI61>.

Read full chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780080449920005022

Six-membered Rings with Two Heteroatoms, and their Fused Carbocyclic Derivatives

Tao Cao , ... Jian Jin , in Comprehensive Heterocyclic Chemistry Four, 2022

8.02.12.1.4 Pyrimidine antifungal agents

A common antifungal mechanism involves the inhibition of fungal sterol synthesis via the inhibition of cytochrome P-450-dependent 14a-demethylase conversion of lanosterol to ergosterol. Inhibition of ergosterol synthesis in plough disrupts fungal cell membrane role. 600 Voriconazole is a triazole pyrimidine derivative antifungal with this mechanism of activeness that is used in the treatment of invasive aspergillosis. 601

Antifungal backdrop accept been reported in 2-phenylaminopyrimidines, such equally pyrimethanil, andoprim, cyprodinil, and mepanipyrim (Fig. 11). 602 Antifungal backdrop accept also been ascribed to other 2-aminopyrimidine derivatives, including fermzone, ethirimol, bupirimate, and dimethirimol (Fig. eleven).

Fig. 11

Fig. eleven. Structures of pyrimidine-containing antifungal agents.

Several other classes of pyrimidine-containing antifungal agents accept been developed with diverse mechanisms of activeness. For example, i class of fungicidal agents were adult from strobilurin A, a natural product that inhibits mitochondrial respiration. 603 Commercial examples of these agents include fluoxastrobin and azoxystrobin (Fig. ten). Another class of antifungal agents includes the diphenyl pyrimidin-5-ylmethanol derivatives, such every bit fenamirol, nuarimol, and triarimol, which inhibit sterol biosynthesis in diverse fungal pathogens (Fig. xi). 603

Finally, a form of peptidyl nucleosides, known equally the polyoxins, represents a serial of important antifungal agents that have been of particular interest as they disrupt fungal jail cell wall synthesis by inhibiting chitin synthetase. 603 These compounds were initially isolated from Streptomyces cacaoi var. asoensis, just are at present produced by fermentation.

Read full affiliate

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B978012818655800041X

Cancer, Immunology and Inflammation, and Infectious Affliction

K. Birch , G. Sibley , in Comprehensive Medicinal Chemistry III, 2017

five.22.5 Summary

Systemic antifungal drug discovery and development has historically lagged backside that of antibacterials. Numerically, the number of systemic antifungal infections is low and would rank equally an orphan disease indication for all species causing disease, and in the last century bloodshed rates from invasive candidiasis and invasive aspergillosis infections approached lxxx%.

The plough of the 21st century saw the introduction of 3rd-generation azoles such as voriconazole and posaconazole which transformed treatment for invasive aspergillosis, reducing mortality rates considerably. Similarly, the introduction of the echinocandins provided an effective alternative treatment for invasive candidiasis, once more reducing mortality. These two classes of agents along with AmB remain the totality of the antifungal armamentarium for systemic fungal infections. The emergence of global resistance within the aspergilli, increasing yr on year, has bandage doubt on the future of the azoles as a frontline therapy. Similarly changes in the epidemiology and the emergence of echinocandin resistance have led to reduced effectiveness of current agents for the treatment of candidiasis. Given that only three classes of antifungals are used to treat these diseases, new agents with alternating mechanisms are desperately needed.

Antifungal drug research and development has entered a new era with multiple new compounds in clinical evolution. Several target known mechanisms, for example, VT-1161, SCY-078, and CD101, and these agents may overcome the resistance issues seen with electric current agents. Other compounds in evolution are new chemical classes and deed via completely new mechanisms. By inhibiting new cellular targets, F901318, APX001, and VL-2397 have the potential to make a bigger therapeutic touch on, particularly against infections where current agents are of little utilize.

Read full chapter

URL:

https://www.sciencedirect.com/science/commodity/pii/B9780124095472124102

Heterocycles and Medicine

Yong-Jin Wu , in Progress in Heterocyclic Chemistry, 2012

1.vii Triazole

The triazole antifungal agents were derived from imidazoles such as clotriazole and miconazole, which were introduced in the 1970s as the first orally bioavailable, broad-spectrum antifungal agents. These agents work by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes (more specifically, by inhibiting the cytochrome P450 fungal enzyme C-14α-dimethylase). However, these imidazole drugs are efficacious simply against superficial fungal infections and also show poor oral bioavailability due to their high liphophilicity. Thus, meaning efforts had gone into the evolution of the antifungal agents that can treat both superficial and life-threatening systemic infections and could be dosed both orally and intravenously. These efforts in the 1980s and 1990s led to the discovery of the triazole antifungal amanuensis, fluconazole (Diflucan™), which carries lower toxicity compared with previous antifungal therapies. Fluconazole binds tightly to the iron centre of the fungal cytochrome P450 enzyme with i of the triazole nitrogens coordinating to the iron ion. Unfortunately, triazole-resistant fungal strains have already been emerged, and there continues to be limited therapeutic choices for a number of mycoses that crusade significant illness in humans. To this end, two new agents, voriconazole (Vfend™) and posaconazole (Noxafil™), which appear to accept expanded antifungal action compared with prior azoles, have been adult <05DT91>. Structurally, replacement of one triazole in fluconazole with pyrimidine band provides voriconazole.

Aprepitant (Emend™) is an antiemetic agent that mediates its effect by blocking the neurokinin 1 (NKi) receptor (come across Section ane.14, vide infra). The triazolone moiety linked to the morpholine nitrogen past a methylene spacer plays two important roles. Outset, this electron-withdrawing heterocycle reduces the basicity of the nitrogen, thus decreasing L-type calcium aqueduct affinity (which is implicated as a possible source of the antinociceptive and anti-inflammatory activities of compounds in this construction course). Second, information technology dramatically increases the binding potency to NK1 receptors.

Sitagliptin (Januvia™), a triazolopiperazine analog, was approved for the treatment of type 2 diabetes <07NRDD109>. Information technology is the first in a new class of drugs that inhibit the proteolytic activeness of dipeptidyl peptidase-4 (DPP-IV), thereby potentiating the activity of endogenous glucoregulatory peptides, known equally incretins. Sitagliptin originated from a structurally distinct screening atomic number 82 8 <04BMCL4763, 05JMC141>. Incorporation of a (R)-β-amino amide moiety into the left-paw side of viii gives ascension to a marked boost in DPP-Iv inhibitory authority as exemplified by 9. Simplification of the molecule and incorporation of multiple fluorine atoms on the phenyl band provides low molecular weight analogs such as chemical compound 10, which exhibits high DPP-IV inhibitory authorization just poor pharmacokinetic backdrop, presumably resulting from extensive metabolism of the heterocyclic moiety. The strategy to ameliorate both metabolic stability and pharmacokinetic backdrop was to replace piperazine moieties with metabolically stable heterocycles in the inhibitor pattern, in detail, using fused heterocycles as piperazine replacements. These studies identified triazolopiperazine heterocycle, and subsequent SAR studies of the triazolopiperazine-based DPP-IV inhibitors led to the discovery of sitagliptin. This compound is structurally very different from saxagliptin (Onglyza™), another DPP-4 inhibitor currently on the market.

Deferasirox (Exjade™) is an orally active iron chelator to reduce chronic iron overload in patients who are receiving long-term blood transfusions. Rufinamide (Inovelon™) is an anticonvulsant used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Maraviroc (Selzentry™) is a CCR5 receptor antagonist course for the handling of HIV infection.

Read full chapter

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780080968070000014