Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.

Exploration of 7-azaindole-coumaranone hybrids and their analogues as protein kinase inhibitors.

7-Azaindole has been labelled a privileged scaffold for the design of new potent inhibitors of protein kinases. In this paper, we determined the inhibition profiles of novel mono- and disubstituted derivatives of 7-azaindole-coumaranone hybrids on various disease-related protein kinases. Eight hit compounds were identified, including a potent Haspin inhibitor with an IC50 value of 0.15 µM. An interesting observation was that all active monosubstituted compounds displayed dual inhibition for Haspin and GSK-3ß, while disubstituted derivatives inhibited GSK-3ß and LmCK1 from Leishmania major parasite. Analyses of structure activity relationships (SARs) also revealed that mono-substitution with para-fluorobenzyloxy ring produced an equipotent inhibition of Haspin and GSK-3ß. Haspin and GSK-3ß are relevant targets for developing new anticancer agents while LmCK1 is an innovative target for leishmanicidal drugs. Novel compounds reported in this paper constitute promising starting points for the development of new anticancer and leishmanicidal drugs.

ABCB1 and ABCG2 Restrict Brain and Testis Accumulation and, Alongside CYP3A, Limit Oral Availability of the Novel TRK Inhibitor Selitrectinib.

Selitrectinib (BAY2731954; LOXO-195) is a promising oral tropomyosin receptor kinase (TRK) inhibitor currently in phase I/II clinical trials for the treatment of histology-agnostic cancers positive for TRK fusions. With therapeutic resistance eventually developing with first-generation TRK inhibitors, selitrectinib was designed to overcome resistance mediated by acquired kinase domain mutations. Using genetically modified mouse models and pharmacological inhibitors, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzyme complex in selitrectinib pharmacokinetics. In vitro, selitrectinib was markedly transported by mouse Abcg2 and human ABCB1, and modestly by human ABCG2. Following oral administration at 10 mg/kg, selitrectinib brain-to-plasma ratios were increased in Abcb1a/1b-/- (twofold) and Abcb1a/1b;Abcg2-/- (5.8-fold) compared with wild-type mice, but not in single Abcg2-/- mice. Testis distribution showed similar results. mAbcb1a/1b and mAbcg2 each restricted the plasma exposure of selitrectinib: With both systems absent oral availability increased by 1.7-fold. Oral administration of the ABCB1/ABCG2 inhibitor elacridar boosted plasma exposure and brain accumulation in wild-type mice to the same levels as seen in Abcb1a/1b;Abcg2-/- mice. In Cyp3a-/- mice, plasma exposure of selitrectinib over 4 hours was increased by 1.4-fold and subsequently reduced by 2.3-fold upon transgenic overexpression of human CYP3A4 in liver and intestine. The relative tissue distribution of selitrectinib remained unaltered. Thus, selitrectinib brain accumulation and oral availability are substantially restricted by ABCB1 and ABCG2, and this can be reversed by pharmacological inhibition. Moreover, oral availability of selitrectinib is limited by CYP3A activity. These insights may be useful to optimize the clinical application of selitrectinib.

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors.

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ1 receptor ligands. All seven ligands exhibited nanomolar affinity for σ1 receptors (Ki(σ1) = 0.47 - 12.1 nM) and moderate selectivity over σ2 receptors (Ki(σ2)/ Ki(σ1) = 2 - 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [18F]8 was prepared via nucleophilic 18F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of greater than 99%, and molar activity of 94 - 121 GBq/µmol. Biodistribution studies of [18F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% - 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ1 receptor-rich brain areas. These findings suggest that [18F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ1 receptors.

Dual-responsive click-crosslinked micelles designed for enhanced chemotherapy for solid tumors.

The design of multiple stimuli-responsive, stable polymeric drug carriers is key for efficient drug release against solid tumors. Herein, core-crosslinked micelles were readily prepared from a pair of redox/pH-sensitive clickable copolymers. The two copolymers comprised the same poly(ethylene glycol) (PEG)-poly(ε-benzyloxycarbonyl-l-lysine) (PZLL) block but with either disulfide-linked azadibenzocyclooctyne (DBCO) or azide (AZ) group-tagged branched polyethylenimine (BPEI, 1.8 kDa). The data showed that an equivalent of the two copolymers could self-assemble into nanosized micelles with the crosslinked core via the DBCO-AZ click chemistry. The click-crosslinked micelles showed excellent size stability under multiple dilutions but destabilization in an acidic or reductive environment. Besides, they could load doxorubicin (DOX), an anticancer drug, and mediate slow drug release in a neutral environment but sufficient drug unloading under acidic plus reductive conditions. In vitro, DOX-loaded crosslinked micelles led to higher DOX accumulation in the cellular nucleus in comparison with non-crosslinked micelles from the PEG-PZLL-BPEI copolymer (PP), thus causing more marked cytotoxicity in SKOV-3 cells. In vivo, DOX-loaded crosslinked micelles caused significant growth inhibition of SKOV-3 tumors xenografted in BALB/c nude mice, and showed superior anticancer efficacy to non-crosslinked PP micelles. Chemotherapy with core-crosslinked micelles had no adverse side effects on the health (serum levels and body weight) of the mice. This study highlights the design of clickable block copolymers to easily construct core-crosslinked and multiple stimuli-responsive micelles for enhanced anticancer therapy.

[Pharmacokinetic properties of an innovative nootropic agent based on a derivative of 3,7-diazabicyclo[3.3.1]nonane]. / Farmakokineticheskie svoistva veshchestva na osnove proizvodnogo 3,7-diazabitsiklo[3.3.1]nonana.

The pharmacokinetics and bioavailability of a derivative of 3,7-diazabicyclo[3.3.1]nonane exhibiting a nootropic effect, were studied after a single dose to rats. The pharmacokinetics of the compound was studied after oral and intravenous administration to 270 male rats Sprague Dawley at doses of 2.5 mg/kg, 13 mg/kg and 25 mg/kg. Its distribution in organs and tissues (brain, thymus, heart, lungs, liver, kidneys, and spleen) was also investigated. It was found that after a single intravenous administration, the investigated substance was determined in the blood of animals for 24 h; the half-life was 4.69 h. The relative bioavailability of the 3,7-diazabicyclo[3.3.1]nonane derivative after oral administration was 42.3%, thus suggesting the prospect of creating dosage forms for oral administration. After a single oral administration, the dose dependence of AUC0-t was exponential. The substance is characterized by heterogeneous distribution in the body with preferential accumulation mainly in well-vascularized tissues.

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

A study of the pharmacokinetics of moxifloxacin by the dynamics of its distribution in the blood plasma and saliva of healthy volunteers: a comparative analysis and possible extrapolation methods.

OBJECTIVES: The pharmacokinetics of moxifloxacin in plasma and saliva was investigated in this study. METHODS: The pharmacokinetics of two specialty drugs of moxifloxacin - reference (Ref) and test (Test) preparation - was studied in 18 healthy volunteers after a single oral dose of 400 mg. RESULTS: It was found that the concentration of moxifloxacin in saliva 3-24 h after taking the drugs was statistically significantly higher than that in plasma. A high correlation was observed between the concentration of moxifloxacin in plasma and saliva of volunteers after taking of Ref and Test. Some pharmacokinetic parameters, calculated by the concentration of moxifloxacin in saliva and plasma, are statistically different. A technique is proposed for extrapolating the concentration of moxifloxacin in plasma according to its concentration in saliva using the established linear relationship between the moxifloxacin in plasma and saliva of volunteers in time interval of 3-24 h after taking Ref. Based on the obtained extrapolated concentration of moxifloxacin, the pharmacokinetic parameters were calculated for two studied drugs and did not statistically differ from the parameters calculated according to the data in plasma. CONCLUSIONS: The developed method of concentration extrapolation allows the use of saliva for pharmacokinetic studies of the tablet preparations of moxifloxacin.

Trans-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging.

Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.

High-Spin Diradical Dication of Chiral π-Conjugated Double Helical Molecule.

We report an air-stable diradical dication of chiral D2-symmetric conjoined bis[5]diazahelicene with an unprecedented high-spin (triplet) ground state, singlet triplet energy gap, ΔEST = 0.3 kcal mol-1. The diradical dication possesses closed-shell (Kekulé) resonance forms with 16 π-electron perimeters. The diradical dication is monomeric in dibutyl phthalate (DBP) matrix at low temperatures, and it has a half-life of more than 2 weeks at ambient conditions in the presence of excess oxidant. A barrier of ∼35 kcal mol-1 has been experimentally determined for inversion of configuration in the neutral conjoined bis[5]diazahelicene, while the inversion barriers in its radical cation and diradical dication were predicted by the DFT computations to be within a few kcal mol-1 of that in the neutral species. Chiral HPLC resolution provides the chiral D2-symmetric conjoined bis[5]diazahelicene, enriched in (P,P)- or (M,M)-enantiomers. The enantiomerically enriched triplet diradical dication is configurationally stable for 48 h at room temperature, thus providing the lower limit for inversion barrier of configuration of 27 kcal mol-1. The enantiomers of conjoined bis[5]diazahelicene and its diradical dication show strong chirooptical properties that are comparable to [6]helicene or carbon-sulfur [7]helicene, as determined by the anisotropy factors, |g| = |Δε|/ε = 0.007 at 348 nm (neutral) and |g| = 0.005 at 385 nm (diradical dication). DFT computations of the radical cation suggest that SOMO and HOMO energy levels are near-degenerate.

Bioanalytical assay for the novel TRK inhibitor selitrectinib in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry.

Selitrectinib is a next generation tropomyosin receptor kinase (TRK) inhibitor developed to overcome acquired resistance to first generation TRK inhibitors. The drug is a cyclic analogue of larotrectinib. An existing bioanalytical assay for larotrectinib was therefore redesigned for selitrectinib. The assay used liquid chromatography-electrospray tandem mass spectrometry in positive selected reaction monitoring mode. Mouse plasma and tissue homogenates of brain, heart, kidney, liver, lung, small intestine, spleen, and testis were pretreated using acetonitrile protein precipitation with larotrectinib added as internal standard. Successful validation using current guidelines was obtained in the range 0.5-1000 ng/ml. Precision was within 5-12% and accuracy within 91-108% for all matrices investigated. The drug was stable in all matrices under the relevant storage conditions. Pharmacokinetics and tissue distribution of selitrectinib were monitored in a pilot study in mice demonstrating the applicability of the presented assay.

Heck functionalization of an asymmetric aza-BODIPY core: synthesis of far-red infrared probes for bioimaging applications.

As part of our ongoing work on the synthesis of a new class of plant hormones named Strigolactones (SLs) and their analogues, we became interested in tracing bioactive molecules with red emitting BODIPY fluorophores in order to unravel signaling and distribution of SLs in plants. In this paper we report on an unprecedented Heck functionalization of azadipyrromethenes (aza-DIPY) which allows for the introduction of suitable functional groups to convert aza-BODIPY in bioconjugate complexes useful for untangling biological processes.

A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R-phencynonate, by stable isotope-dilution LC-MS/MS and its application to bioavailability and dose proportionality studies.

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.

Degradation kinetics and pathways of spirotetramat in different parts of spinach plant and in the soil.

Spirotetramat is a new pesticide against a broad spectrum of sucking insects and exhibits a unique property with a two-way systemicity. In order to formulate a scientific rationale for a reasonable spray dose and the safe interval period of 22.4 % spirotetramat suspension concentrate on controlling vegetable pests, we analyzed degradation dynamics and pathways of spirotetramat in different parts of spinach plant (leaf, stalk, and root) and in the soil. We conducted experimental trials under field conditions and adopted a simple and reliable method (dispersive solid phase extraction) combined with liquid chromatography-triple quadrupole tandem mass spectrometry to evaluate the dissipation rates of spirotetramat residue and its metabolites. The results showed that the spirotetramat was degraded into different metabolite residues in different parts of spinach plant (leaf, stalk, and root) and in the soil. Specifically, spirotetramat was degraded into B-keto, B-glu, and B-enol in the leaf; B-glu and B-enol in the stalk; and only B-enol in the root. In the soil where the plants grew, spirotetramat followed a completely different pathway compared to the plant and degraded into B-keto and B-mono. Regardless of different degradation pathways, the dissipation dynamic equations of spirotetramat in different parts of spinach plant and in the soil were all based on the first-order reaction dynamic equations. This work provides guidelines for the safe use of spirotetramat in spinach fields, which would help prevent potential health threats to consumers.

Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation.

Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with (64)Cu. In vitro stability and cellular uptake of (64)Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with (64)Cu. N-NE3TA-Tf rapidly bound to (64)Cu (>98% radiolabeling efficiency, 1min, RT), and (64)Cu-N-NE3TA-Tf remained stable in human serum for 2days and demonstrated high uptake in PC-3 cancer cells. (64)Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24h period. This bifunctional chelate presents highly efficient chelation chemistry with (64)Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with (64)Cu for potential use in PET imaging applications.

Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example.

Two benzazaborinine analogues of propranolol were synthesized and extensively profiled in vitro and in vivo. These analogues showed potency and physicochemical and in vitro ADME-tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs.

Synthesis and assessment of a maleimide functionalized BF2 azadipyrromethene near-infrared fluorochrome.

The first water soluble maleimide bearing NIR BF2-azadipyrromethene (NIR-AZA) fluorochrome has been synthesised which is capable of rapid thiol conjugations in water with peptides such as glutathione, the cell penetrating peptide (CPP) C(ß-A)SKKKKTKV-NH2 and a thiol substituted cRGD. NIR fluorescence imaging showed rapid cellular delivery of the CPP conjugate and effective in vivo tumour localization for the cRGD conjugate.

Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors.

Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

Ranking the Binding Energies of p53 Mutant Activators and Their ADMET Properties.

The guardian of the genome, p53, is the most mutated protein found in all cancer cells. Restoration of wild-type activity to mutant p53 offers promise to eradicate cancer cells using novel pharmacological agents. Several molecules have already been found to activate mutant p53. While the exact mechanism of action of these compounds has not been fully understood, a transiently open pocket has been identified in some mutants. In our study, we docked twelve known activators to p53 into the open pocket to further understand their mechanism of action and rank the best binders. In addition, we predicted the absorption, distribution, metabolism, excretion and toxicity properties of these compounds to assess their pharmaceutical usefulness. Our studies showed that alkylating ligands do not all bind at the same position, probably due to their varying sizes. In addition, we found that non-alkylating ligands are capable of binding at the same pocket and directly interacting with Cys124. The comparison of the different ligands demonstrates that stictic acid has a great potential as a p53 activator in terms of less adverse effects although it has poorer pharmacokinetic properties.