Scientia Pharmaceutica

11 pages, 678 KB

Open AccessArticle

Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method

by Abdel Naser Zaid, Rowa Al Ramahi, Rita Cortesi, Ayman Mousa, Nidal Jaradat, Nadia Ghazal and Rana Bustami

Sci. Pharm. 2016, 84(3), 536-546; https://doi.org/10.3390/scipharm84030536 - 30 Jun 2016

Cited by 7 | Viewed by 7686

Abstract

There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The [...] Read more.

There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The aim of this study is to demonstrate the interchangeability between two generic RC 20 mg film-coated tablets under fasting conditions among Mediterranean Arabs and to compare the pharmacokinetic results with Asian and Caucasian subjects from other studies. A single oral RC 20 mg dose, randomized, open-label, two-way crossover design study was conducted in 30 healthy Mediterranean Arab volunteers. Blood samples were collected prior to dosing and over a 72-h period. Concentrations in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method. Twenty-six volunteers completed the study. Statistical comparison of the main PK parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric mean %) were 107.73 (96.57–120.17), 103.61 (94.03–114.16), and 104.23 (94.84–114.54) for peak plasma concentration (C_max), Area Under the Curve (AUC)_0→last, and AUC_0→∞, respectively. The 90% confidence intervals were within the pre-defined limits of 80%–125% as specified by the Food and Drug Administration and European Medicines Agency for bioequivalence studies. Both formulations were well-tolerated and no serious adverse events were reported. The PK results (AUC_0→last and C_max) were close to those of the Caucasian subjects. This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 20 mg oral dose of RC under fasting conditions. Both formulations also showed comparable safety results. The PK results of the test and reference in the study subjects fall within the acceptable interval of 80%–125% and they were very close to the results among Caucasians. These PK results may be useful in order to determine the suitable RC dose among Arab Mediterranean patients. Full article

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13 pages, 3149 KB

Open AccessArticle

Synthesis, Structure, and Analgesic Properties of Halogen-Substituted 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides

by Igor V. Ukrainets, Lidiya A. Petrushova, Svitlana V. Shishkina, Lyudmila V. Sidorenko, Galina Sim and Olga V. Kryvanych

Sci. Pharm. 2016, 84(3), 523-535; https://doi.org/10.3390/scipharm84030523 - 17 Jun 2016

Cited by 4 | Viewed by 4182

Abstract

As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (¹ [...] Read more.

As potential new analgesics, the corresponding 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides have been obtained by amidation of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with aniline and its halogenated analogsin boiling dry xylene. The peculiarities of the mass and nuclear magnetic resonance (¹Н and ¹³С) spectra of the synthesized compounds are discussed. Using X-ray diffraction analysis, the ability of the compounds to form stable solvates with N,N-dimethylformamide has been shown on the example of 4-bromo-substituted derivative. It should be further studied to be considered in their crystallization. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick (tail immersion test) among halogen-substituted 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxanilides, substances which are considerably superior to meloxicam and piroxicam by their analgesic activity have been found. They are of interest for further profound studies. Full article

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9 pages, 883 KB

Open AccessArticle

Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers

by Mercè Cánovas, Francisco Polonio and Francesc Cabré

Sci. Pharm. 2016, 84(3), 514-522; https://doi.org/10.3390/scipharm84030514 - 13 Jun 2016

Cited by 2 | Viewed by 5559

Abstract

The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions [...] Read more.

The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC_0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and C_max (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The t_max (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC_0-t and C_max were within the bioequivalence acceptance range of 80%–125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt^® Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics. Full article

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7 pages, 802 KB

Open AccessArticle

Anomalous Separation of Small Y-Chromosomal DNA Fragments on Microchip Electrophoresis

by Mohammad Jabasini, Ashraf Ewis, Youichi Sato, Yutaka Nakahori and Yoshinobu Baba

Sci. Pharm. 2016, 84(3), 507-513; https://doi.org/10.3390/scipharm84030507 - 26 May 2016

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Abstract

We investigated an anomalous DNA separation where two DNA fragments from the human Y-chromosome sY638 (64 bp) and sY592 (65 bp), with only one base pair difference, were separated. This result is abnormal since in a previous study, we found that 5 bp [...] Read more.

We investigated an anomalous DNA separation where two DNA fragments from the human Y-chromosome sY638 (64 bp) and sY592 (65 bp), with only one base pair difference, were separated. This result is abnormal since in a previous study, we found that 5 bp was the minimum difference between two DNA fragments that the microchip electrophoresis system can separate. The formation of a mini-loop in the structure of the DNA fragment of sY638 (64 bp) was strongly expected to be the reason. To investigate this, we synthesized three modified DNA fragments for sY638 (64 bp), and the modifications were in two expected locations for possible mini-loop formation. Later, the separation between sY592 (65 bp) and the three modified fragments of sY638 (64 bp) was not possible. Thus, we conclude that the formation of a mini-loop in the structure of the DNA is the reason behind this anomalous separation. Full article

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18 pages, 2360 KB

Open AccessArticle

Quality Control of Traditional Cannabis Tinctures: Pattern, Markers, and Stability

by Wieland Peschel

Sci. Pharm. 2016, 84(3), 567-584; https://doi.org/10.3390/scipharm84030567 - 18 Apr 2016

Cited by 33 | Viewed by 15521

Abstract

Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a Δ9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography [...] Read more.

Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a Δ9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography with diode-array detection (HPLC/DAD) was used to determine THC, Δ9-tetrahydrocannabinolic acid A (THCA), cannabinol (CBN), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannflavin A/B, and total phenolics. Derived group and ratio markers describe absolute and relative profiles when varying plant part (flos, folium), extraction solvent (EtOH percentage), storage conditions (‘shelf’ or ‘fridge’ up to 15 months), and pasteurization (2 h 70 °C, 20 min 80 °C). Tinctures from female flowering tops contained ten-fold more cannabinoids than tinctures from leaves; tinctures (80%–90% EtOH) contained ten-fold more cannabinoids than tinctures (40% EtOH). The analysis of CBGA + CBG, the main co-cannabinoids aside from THCA + THC, appears more relevant than CBDA + CBD. The decarboxylation of THCA to THC—the main change during storage of freshly prepared tinctures—is after 15 months in the ‘fridge’ comparable to 3 months on the ‘shelf’. Minimally increased CBN totals did not correlate to diminished totals of THCA and THC (up to 15% after 3 months ‘shelf’, 45% after 15 months ‘fridge’). Instead, total cannabinoids or acidic/neutral cannabinoid ratios are better stability markers. Moderate changes after pasteurization and partial losses below 10% for total cannabinoids after 9 months ‘fridge’ indicate possibilities for a reasonable shelf life. Yet storage and use of non-stabilized tinctures remain critical without authorized specification and stability data because a consistent cannabinoid content is not guaranteed. Full article

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10 pages, 2863 KB

Open AccessArticle

The Study of Structure—Analgesic Activity Relationships in a Series of 4-Hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic Acid Toluidides and Xylidides

by Igor V. Ukrainets, Lidiya A. Petrushova, Lyudmila V. Sidorenko, Alexandra A. Davidenko and Marina A. Duchenko

Sci. Pharm. 2016, 84(3), 497-506; https://doi.org/10.3390/scipharm84030497 - 18 Apr 2016

Cited by 9 | Viewed by 4113

Abstract

In continuing the search for new analgesics among derivatives of 2,1-benzothiazines, a series of corresponding toluidides and xylidides of 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid has been synthesized by the reaction of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with equimolar amounts of mono- [...] Read more.

In continuing the search for new analgesics among derivatives of 2,1-benzothiazines, a series of corresponding toluidides and xylidides of 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylic acid has been synthesized by the reaction of ethyl 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxylate with equimolar amounts of mono- and dimethyl-substituted anilides in boiling dry xylene. Their structure has been confirmed by the data of elemental analysis, nuclear magnetic resonance (NMR) spectroscopy (¹Н and ¹³С), as well as mass spectrometry. All compounds obtained were subjected to pharmacological screening to identify their analgesic properties. Testing was carried out in male rats using the standard model of the thermal tail-flick (tail immersion test) in parallel and in comparison with the structurally related drugs meloxicam and piroxicam. Among the substances studied, highly active oral painkillers have been found; they exceed the analgesic effect of the reference drugs using the same dose. Interesting structural and biological regularities have been described; they will be useful in further research on creating promising new analgesics based on 4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides. Full article

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12 pages, 1335 KB

Open AccessArticle

Metabolite Profiles in Various Plant Organs of Justicia gendarussa Burm.f. and Its in Vitro Cultures

by Putu Indrayoni, Diah Intan Purwanti, Suwidji Wongso, Bambang E.W. Prajogo and Gunawan Indrayanto

Sci. Pharm. 2016, 84(3), 555-566; https://doi.org/10.3390/scipharm84030555 - 13 Apr 2016

Cited by 5 | Viewed by 5211

Abstract

Metabolite profiles of plant organs and their in vitro cultures of Justicia gendarussa have been studied by using Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight-Mass Spectrometry (UPLC-Qtof-MS). Samples of leaves, stems, roots, and shoot cultures showed similar patterns of metabolites, while samples of root cultures [...] Read more.

Metabolite profiles of plant organs and their in vitro cultures of Justicia gendarussa have been studied by using Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight-Mass Spectrometry (UPLC-Qtof-MS). Samples of leaves, stems, roots, and shoot cultures showed similar patterns of metabolites, while samples of root cultures gave very different profiles. Concentrations of secondary metabolites in shoot cultures were relatively low compared to those in the leaves and roots of the plants. The results suggested that secondary metabolites in J. gendarussa were biosynthetized in the leaves, then transported to the roots. Full article

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13 pages, 6080 KB

Open AccessArticle

Benzotriazole-Mediated Synthesis and Antibacterial Activity of Novel N-Acylcephalexins

by Khalid A. Agha, Nader E. Abo-Dya, Tarek S. Ibrahim, Eatedal H. Abdel-Aal and Wael A. Hegazy

Sci. Pharm. 2016, 84(3), 484-496; https://doi.org/10.3390/scipharm84030484 - 13 Apr 2016

Cited by 34 | Viewed by 4560

Abstract

Cephalexin (1) was acylated using N-acylbenzotriazoles (3a–k′) derived from various carboxylic acids including aromatic, heterocyclic and N-Pg-α-amino acid to afford N-acylcephalexins in excellent yields (82%–96%). Antibacterial screening of the novel cephalosporins revealed that all [...] Read more.

Cephalexin (1) was acylated using N-acylbenzotriazoles (3a–k′) derived from various carboxylic acids including aromatic, heterocyclic and N-Pg-α-amino acid to afford N-acylcephalexins in excellent yields (82%–96%). Antibacterial screening of the novel cephalosporins revealed that all targets (4a–j) retained the antibacterial activity of cephalexin against Staphylococcus aureus (ATCC 6538). N-Nicotinylcephalexin (4c) and N-(3,4,5-trimethoxybenzoyl)cephalexin (4g) exhibited a broader spectrum of antibacterial activity towards standard strains of Staphylococcus aureus (ATCC 6538), Paenibacillus polymyxa (ATCC 842), and Escherichia coli (ATCC 10536) as well as a resistant strain of Pseudomonas aeruginosa (ATCC 27853). Full article

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19 pages, 6809 KB

Open AccessReview

Estrogen Receptor Ligands: A Review (2013–2015)

by Shabnam Farzaneh and Afshin Zarghi

Sci. Pharm. 2016, 84(3), 409-427; https://doi.org/10.3390/scipharm84030409 - 13 Apr 2016

Cited by 60 | Viewed by 7593

Abstract

Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors. [...] Read more.

Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors. Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular and tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and tissues, and they control key physiological functions in various organ systems. Estrogens attract great attention due to their wide applications in female reproductive functions and treatment of some estrogen-dependent cancers and osteoporosis. This paper provides a general review of ER ligands published in international journals patented between 2013 and 2015. The broad physiological profile of estrogens has attracted the attention of many researchers to develop new estrogen ligands as therapeutic molecules for various clinical purposes. After the discovery of the ERβ receptor, subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse side effects, based on the different distributions and relative levels of the two ER subtypes in different estrogen target tissues. Therefore, recent literature has focused on selective estrogen ligands as highly promising agents for the treatment of some types of cancer, as well as for cardiovascular, inflammatory, and neurodegenerative diseases. Estrogen receptors are nuclear transcription factors that are involved in the regulation of many complex physiological functions in humans. Selective estrogen ligands are highly promising targets for treatment of some types of cancer, as well as for cardiovascular, inflammatory and neurodegenerative diseases. Extensive structure-activity relationship studies of ER ligands based on small molecules indicate that many different structural scaffolds may provide high-affinity compounds, provided that some basic structural requirements are present. Full article

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8 pages, 202 KB

Open AccessArticle

In Vivo Anticonvulsant Activity of Extracts and Protopine from the Fumaria schleicheri Herb

by Yuliya Prokopenko, Vadim Tsyvunin, Sergey Shtrygol’ and Victoriya Georgiyants

Sci. Pharm. 2016, 84(3), 547-554; https://doi.org/10.3390/scipharm84030547 - 6 Dec 2015

Cited by 19 | Viewed by 4111

Abstract

The present study aimed to investigate the role of several biologically active compounds from Fumaria schleicheri Soy.-Will. in anticonvulsant models. The flavonoid fraction, alkaloid fraction, individual alkaloid protopine, and polysaccharide-protein complex were isolated from the Fumaria schleicheri herb and studied along with Fumaria [...] Read more.

The present study aimed to investigate the role of several biologically active compounds from Fumaria schleicheri Soy.-Will. in anticonvulsant models. The flavonoid fraction, alkaloid fraction, individual alkaloid protopine, and polysaccharide-protein complex were isolated from the Fumaria schleicheri herb and studied along with Fumaria schleicheri dry extract in mice with pentylenetetrazole-induced seizures. According to empirical results, the expressed anticonvulsant effect of Fumaria schleicheri dry extract depends on the synergism of biologically active compounds in herbal medicine, although some individual substances (mostly protopine and the protein-polysaccharide fraction) have shown moderate anti-seizure activity. Full article

17 pages, 6642 KB

Open AccessArticle

Synthesis and Biological Activities of Camphor Hydrazone and Imine Derivatives

by Emerson T. Da Silva, Adriele Da Silva Araújo, Adriana M. Moraes, Leidiane A. De Souza, Maria Cristina Silva Lourenço, Marcus V. N. De Souza, James L. Wardell and Solange M. S. V. Wardell

Sci. Pharm. 2016, 84(3), 467-483; https://doi.org/10.3390/scipharm84030467 - 18 Oct 2015

Cited by 31 | Viewed by 7435

Abstract

Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C₉H₁₆C=O, into a number of derivatives including hydrazones, C₉H₁₆C=N-NHAr 3, imines, C₉H₁₆C=N-R 7, and the key intermediate [...] Read more.

Both sonochemical and classical methodologies have been employed to convert camphor, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one, C₉H₁₆C=O, into a number of derivatives including hydrazones, C₉H₁₆C=N-NHAr 3, imines, C₉H₁₆C=N-R 7, and the key intermediate nitroimine, C₉H₁₆C=N-NO₂ 6. Reactions of nitroamine 6 with nucleophiles by classical methods provided the desired compounds in a range of yields. In evaluations of activity against Mycobacterium tuberculosis, compound 7j exhibited the best activity (minimal inhibitory concentration (MIC) = 3.12 µg/mL), comparable to that of the antitubercular drug ethambutol. The other derivatives displayed modest antimycobacterial activities at 25–50 µg/mL. In in vitro tests against cancer cell lines, none of the synthesized camphor compounds exhibited cytotoxic activities. Full article

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11 pages, 2157 KB

Open AccessArticle

Trace Level Quantification of the (−)2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol Genotoxic Impurity in Efavirenz Drug Substance and Drug Product Using LC–MS/MS

by Nagadeep Jaishetty, Kamaraj Palanisamy, Arthanareeswari Maruthapillai and Rajamanohar Jaishetty

Sci. Pharm. 2016, 84(3), 456-466; https://doi.org/10.3390/scipharm84030456 - 18 Oct 2015

Cited by 7 | Viewed by 5847

Abstract

Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus type-1 (HIV). (2S)-(2-Amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (AMCOL), used as an intermediate in the synthesis of efavirenz and a degradation impurity, has an aminoaryl derivative which is a well-known alerting function for [...] Read more.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus type-1 (HIV). (2S)-(2-Amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (AMCOL), used as an intermediate in the synthesis of efavirenz and a degradation impurity, has an aminoaryl derivative which is a well-known alerting function for genotoxic activity. Upon request from a regulatory agency, a selective and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for trace level quantitative determination of AMCOL related compound of efavirenz, for a risk assessment and comparison of impurity levels with the commercially available innovator product (brand name: Sustiva). The method provided excellent sensitivity at a typical target analyte level of <2.5 ppm, an established threshold of toxicological concern (TTC), when the drug substance and drug product samples were prepared at 15.0 mg/mL. The AMCOL sample was analyzed on a Luna C18 (2) (100 mm × 4.6 mm, 3 µm) column interfaced with a triple quadrupole tandem mass spectrometer operated in a multiple reaction monitoring (MRM) mode. Positive electrospray ionization (ESI) was employed as the ionization source and the mobile phase used was 5.0 mM ammonium acetate-methanol (35:65, v/v). The calibration curve showed good linearity over the concentration range of 0.2–5.0 ppm with a correlation coefficient of >0.999. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.07 and 0.2 ppm, respectively. The developed method was validated as per international council on harmonization (ICH) guidelines in terms of LOD, LOQ, linearity, precision, accuracy, specificity, and robustness. Full article

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9 pages, 1349 KB

Open AccessArticle

A Facile, Improved Synthesis of Sildenafil and Its Analogues

by Ambati. V. Raghava Reddy, Garaga Srinivas, Chandiran Takshinamoorthy, Badarinadh Gupta Peruri and Andra Naidu

Sci. Pharm. 2016, 84(3), 447-455; https://doi.org/10.3390/scipharm84030447 - 18 Oct 2015

Cited by 11 | Viewed by 8511

Abstract

This paper describes the facile synthesis of sildenafil citrate (1) and its related compounds through an improved chlorosulfonation reaction using chlorosulfonic acid and thionyl chloride. This synthesis results in pure sildenafil with high yield. The structures of the compounds were determined [...] Read more.

This paper describes the facile synthesis of sildenafil citrate (1) and its related compounds through an improved chlorosulfonation reaction using chlorosulfonic acid and thionyl chloride. This synthesis results in pure sildenafil with high yield. The structures of the compounds were determined with infrared (IR), ¹H-NMR and ¹³C-NMR spectroscopic methods, and high resolution mass spectroscopy (HRMS) analysis. Full article

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19 pages, 3478 KB

Open AccessArticle

Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors

by Ahmed K. Elhady, Sara C. Sigler, Nazih Noureldin, Joshua C. Canzoneri, Nermin S. Ahmed, Gary A. Piazza and Ashraf H. Abadi

Sci. Pharm. 2016, 84(3), 428-446; https://doi.org/10.3390/scipharm84030428 - 26 Sep 2015

Cited by 7 | Viewed by 4269

Abstract

Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione [...] Read more.

Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration. Full article

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Sci. Pharm., Volume 84, Issue 3 (September 2016) – 14 articles , Pages 409-584

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