- Influence of CYP450 Enzymes, CES1, PON1, ABCB1, and P2RY12 Polymorphisms on Clopidogrel Response in Patients Subjected to a Percutaneous Neurointervention. [Journal Article]
- CTClin Ther 2019; 41(6):1199-1212.e2
- CONCLUSIONS: Therapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach.
- Omalizumab For The Treatment of Persistent Drug Induced Urticaria Elicited By Thienopyridines: A Case Report. [Journal Article]
- AAAntiinflamm Antiallergy Agents Med Chem 2019 May 21
- The anti-IgE Omalizumab may be helpful to treat clopidogrel hypersensitivity without stopping thienopyridine administration in patients needing to assume double antiplatelet therapy continuosly after…
The anti-IgE Omalizumab may be helpful to treat clopidogrel hypersensitivity without stopping thienopyridine administration in patients needing to assume double antiplatelet therapy continuosly after coronary stent placement.
- Synthesis and structure-activity relationship of 4-alkoxy-thieno[2,3-b]pyridine derivatives as potent alkaline phosphatase enhancers for osteoporosis treatment. [Journal Article]
- BMBioorg Med Chem Lett 2019 Jul 15; 29(14):1769-1773
- The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thi…
The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30 mg/kg/day.
- Enhanced platelet response to clopidogrel in Zucker diabetic fatty rats due to impaired clopidogrel inactivation by carboxylesterase 1 and increased exposure to active metabolite. [Journal Article]
- DMDrug Metab Dispos 2019 May 15
- Clopidogrel (Clop), a thienopyridine anti-platelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase 1 (CES1) to the inactive Clo…
Clopidogrel (Clop), a thienopyridine anti-platelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase 1 (CES1) to the inactive Clop-acid. Patients with type 2 diabetes (T2DM) tend to have a poor response to Clop due to reduced generation of Clop-AM. Whether a similar response occurs in the Zucker diabetic fatty (ZDF) rat, a commonly used animal model of T2DM, has not been explored. Here, we compared ZDF and control rats for hepatic CES1- and CYP-mediated Clop metabolism, pharmacokinetics of Clop, Clop-AM and Clop-acid, and the anti-platelet efficacy of Clop. In contrast to clinical findings, Clop-treated ZDF rats displayed significantly less (50%) maximum platelet aggregation at 4 h than control rats; the enhanced efficacy was accompanied by higher formation of Clop-AM and lower formation of Clop-acid. In vitro studies showed that hepatic levels of CES1 protein and activity and Ces1e mRNA were significantly lower in ZDF than in control rats, as were the mRNA levels of CYP2B1/2, CYP2C11 and CYP3A2, and levels of CYP2B6-, CYP2C19- and CYP3A4-related proteins and enzymatic activities in liver microsomes of ZDF rats. Interestingly, liver microsomes of ZDF rats produced higher levels of Clop-AM than that of control rats despite their lower CYP levels, though the addition of fluoride ion, an esterase inhibitor, enhanced Clop-AM formation in control rats more than in ZDF rats. These results suggest that the reduction in CES1-based Clop inactivation indirectly enhances Clop efficacy in ZDF rats by making more Clop available for CYP-mediated Clop-AM formation. SIGNIFICANCE STATEMENT: N/A.
- Novel dehydropeptide-based magnetogels containing manganese ferrite nanoparticles as antitumor drug nanocarriers. [Journal Article]
- PCPhys Chem Chem Phys 2019 May 22; 21(20):10377-10390
- Herein, novel dehydropeptide-based magnetogels, based on the hydrogelators Npx-l-Phe-Z-ΔAbu-OH, Npx-l-Trp-Z-ΔPhe-OH and Npx-l-Ala-Z-ΔPhe-Gly-l-Arg-Gly-l-Asp-Gly-OH and containing manganese ferrite na…
Herein, novel dehydropeptide-based magnetogels, based on the hydrogelators Npx-l-Phe-Z-ΔAbu-OH, Npx-l-Trp-Z-ΔPhe-OH and Npx-l-Ala-Z-ΔPhe-Gly-l-Arg-Gly-l-Asp-Gly-OH and containing manganese ferrite nanoparticles (diameters around 20 nm), were prepared and characterized. TEM and FTIR measurements showed that the magnetogels maintained the fibrous structure of neat hydrogels, with fibres of ca. 20 nm average width (generally in the range 10-30 nm) and a few conformational changes relative to the neat hydrogels. The magnetogels were tested as nanocarriers for two potential fluorescent antitumor drugs: a thienopyridine derivative and the natural compound curcumin. FRET (Förster resonance energy transfer) from the aromatic moieties (energy donors) of gels to the fluorescent drugs (energy acceptors) and fluorescence anisotropy measurements confirmed the incorporation of both drugs into the magnetogel matrices. The transport of both drugs loaded into the magnetogels to membrane models (small unilamellar vesicles) was assessed by FRET between the fluorescent drugs and the dye Nile Red. The magnetogel possessing the RGD sequence was most promising for the delivery of the thienopyridine derivative, whereas three magnetogels were found to be suitable for the delivery of curcumin.
- Structural dissection reveals a general mechanistic principle for group II chitinase (ChtII) inhibition. [Journal Article]
- JBJ Biol Chem 2019 Jun 14; 294(24):9358-9364
- Small-molecule inhibitors of insect chitinases have potential applications for controlling insect pests. Insect group II chitinase (ChtII) is the most important chitinase in insects and functions thr…
Small-molecule inhibitors of insect chitinases have potential applications for controlling insect pests. Insect group II chitinase (ChtII) is the most important chitinase in insects and functions throughout all developmental stages. However, the possibility of inhibiting ChtII by small molecules has not been explored yet. Here, we report the structural characteristics of four molecules that exhibited similar levels of inhibitory activity against OfChtII, a group II chitinase from the agricultural pest Asian corn borer Ostrinia furnacalis These inhibitors were chitooctaose ((GlcN)8), dipyrido-pyrimidine derivative (DP), piperidine-thienopyridine derivative (PT), and naphthalimide derivative (NI). The crystal structures of the OfChtII catalytic domain complexed with each of the four inhibitors at 1.4-2.0 Å resolutions suggested they all exhibit similar binding modes within the substrate-binding cleft; specifically, two hydrophobic groups of the inhibitor interact with +1/+2 tryptophan and a -1 hydrophobic pocket. The structure of the (GlcN)8 complex surprisingly revealed that the oligosaccharide chain of the inhibitor is orientated in the opposite direction to that previously observed in complexes with other chitinases. Injection of the inhibitors into 4th instar O. furnacalis larvae led to defects in development and pupation. The results of this study provide insights into a general mechanistic principle that confers inhibitory activity against ChtII, which could facilitate rational design of agrochemicals that target ecdysis of insect pests.
- The Degradation Chemistry of Prasugrel Hydrochloride: Part 1-Drug Substance. [Journal Article]
- JPJ Pharm Sci 2019 Apr 11
- Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride) …
Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride) has been carried out on the drug substance (part I) and on the drug product (part II, future article) using a multidimensional approach including hydrolytic, oxidative, and photolytic stressing, computational chemistry, HPLC analysis, and structure elucidation by various spectroscopic techniques. The major degradation products formed from the drug substance under the various stress conditions have been isolated and structures unambiguously determined, and the pathways leading to these products have been proposed. Fourteen new (not previously disclosed) products were discovered and characterized, in addition to 4 degradation products that had been previously identified in the literature. The pathways indicate that prasugrel is susceptible to hydrolysis, autoxidation (both radical-initiated and single-electron mediated), and peroxide-mediated oxidation; in solution, prasugrel is susceptible to photodegradation.
- Discovery and optimization of thienopyridine derivatives as novel urea transporter inhibitors. [Journal Article]
- EJEur J Med Chem 2019 Jun 15; 172:131-142
- Urea transporters (UTs) play an important role in the urine concentrating mechanism and are recognized as novel targets for developing small molecule inhibitors with salt-sparing diuretic activity. T…
Urea transporters (UTs) play an important role in the urine concentrating mechanism and are recognized as novel targets for developing small molecule inhibitors with salt-sparing diuretic activity. Thienoquinoline derivatives, a class of novel UT-B inhibitors identified by our group, play a significant diuresis in animal model. However, the poor solubility and low bioavailability limited its further development. To overcome these shortcomings, the structure modification of thienoquinoline was carried out in this study, which led to the discovery of novel thienopyridine derivatives as specific urea transporter inhibitors. Further optimization obtained the promising preclinical candidate 8n with not only excellent inhibition effect on urea transporters and diuretic activity on rat model, but also suitable water solubility and Log P value.
- Pharmacology of P2Y receptors. [Review]
- BRBrain Res Bull 2019 Mar 25
- P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes divided into two subgroups (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) and…
P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes divided into two subgroups (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) and (P2Y12, P2Y13, and P2Y14). The P2Y receptors are expressed in various cell types and play important roles in physiology and pathophysiology including inflammatory responses and neuropathic pain. The antagonism of P2Y12 receptors is used in pharmacotherapy for the prevention and therapy of cardiovascular events. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel inhibit platelet P2Y12 receptors and reduce thereby platelet aggregation. The P2Y2 receptor agonist diquafosol is used for the treatment of the dry eye syndrome. The P2Y receptor subtypes differ in their amino acid sequences, their pharmacological profiles and their signaling transduction pathways. Recently, selective receptor ligands have been developed for all subtypes. The published crystal structures of the human P2Y1 and P2Y12 receptors as well as receptor models will facilitate the development of novel drugs for pharmacotherapy.
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- Antithrombotics in stable peripheral artery disease. [Review]
- VMVasc Med 2019; 24(2):132-140
- Patients with peripheral artery disease (PAD) are at high risk for ischemic cardiovascular complications. While single antiplatelet therapy (SAPT), predominantly aspirin, has long been the standard a…
Patients with peripheral artery disease (PAD) are at high risk for ischemic cardiovascular complications. While single antiplatelet therapy (SAPT), predominantly aspirin, has long been the standard antithrombotic treatment in stable PAD, there have now been greater than 40,000 PAD patients randomized to varying antiplatelet and/or anticoagulant regimens. In this review, we provide a summary of the current evidence for antithrombotics in stable PAD, focusing on the rates of major adverse cardiovascular events (MACE), major adverse limb events (MALE), and major bleeding. SAPT has a limited role in the treatment of asymptomatic PAD, particularly in the absence of concomitant coronary artery disease. In symptomatic PAD, SAPT is effective in preventing MACE, though treatment with a thienopyridine appears marginally superior to aspirin. Dual antiplatelet therapy (DAPT) suggests benefit over SAPT in reducing MACE and MALE, though studies to date are not conclusive and/or are associated with excess major bleeding. Combining moderate to high intensity vitamin K antagonists with antiplatelet therapy does not reduce MACE or MALE and increases life-threatening bleeding. Rivaroxaban 2.5 mg BID in addition to aspirin reduces the incidence of both MACE and MALE as compared to aspirin alone, without increasing life-threatening bleeding. This regimen is associated with a reduced severity of MALE when it does occur. Comparisons across antithrombotic trials in PAD are challenging given the heterogeneity of patient populations and the differing assessment of outcomes. The vascular medicine practitioner can reduce ischemic cardiac and limb events, as well as minimize life-threatening bleeding, by choosing the optimal antithrombotic regimen in their PAD patients.