RESUMEN
BACKGROUND: Non-cardioembolic ischemic stroke (NCIS) and ischemic heart disease (IHD) require secondary prevention with antiplatelet therapy (APT). We investigated APT prescription status for patients with NCIS and IHD. RESEARCH DESIGN AND METHODS: This retrospective study utilized claims data from patients with NCIS and those who underwent percutaneous coronary intervention for IHD and received antiplatelet drugs. The study included Phases A (2015-2016), B (2017-2018), and C (2019-2020). We evaluated patient characteristics, APT prescription rates (dual [DAPT] and single [SAPT]), and prescriptions by NCIS subtype. RESULTS: In the NCIS cohort, the initial DAPT prescription rate increased over time (Phase A: 14.9%, B: 19.2%, C: 28.0%), but decreased to 6% after 3 months. Subsequently, 25% of patients did not receive APT. For IHD, DAPT duration decreased over time, with 12-month prescription rates of 48.0%, 43.1%, and 32.6% for Phases A, B, and C, respectively. SAPT prescriptions, predominantly aspirin, increased, and use of P2Y12 inhibitors also rose. Few patients (10%) did not receive APT. CONCLUSIONS: Shorter DAPT duration/earlier switching to SAPT for NCIS and IHD have gained acceptance in regional medical care. A higher proportion of NCIS vs IHD patients did not receive APT in the chronic phase. TRIAL REGISTRATION: UMIN000052198.
RESUMEN
Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.
Asunto(s)
Inhibidores del Factor Xa , Piridinas/síntesis química , Tiazoles/síntesis química , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Factor Xa/química , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Unión Proteica , Tiempo de Protrombina , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Wistar , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
In our investigation of factor Xa inhibitors, a series of 1-(6-chloronaphthalen-2-yl)sulfonyl-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)piperazines 3a-i were synthesized. In vitro inhibitory activities of the compounds against factor Xa and coagulation are summarized. Among the compounds, 3c and 3d, possessing a carbamoyl or N-methylcarbamoyl moiety, showed potent inhibitory activities when administered orally to rats.
Asunto(s)
Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Inhibidores de Proteasas/síntesis química , Piridinas/farmacología , Administración Oral , Animales , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacología , Pruebas de Coagulación Sanguínea , Humanos , Concentración 50 Inhibidora , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacología , Piridinas/síntesis química , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
Beta-adrenergic receptor kinase 1 (betaARK1) and cyclic adenosine 5'-monophosphate-dependent protein kinase A (PKA) have structurally similar adenine-binding pockets but have different physiologic functions. To obtain specific betaARK1 inhibitors, a two step rational drug design process was used. First, a search was conducted on three-dimensional models of commercially available compounds to find compounds that fit the adenine-binding pocket of betaARK1. Second, a comparative docking study that focused on the differences between the adenine-binding pockets of the two enzymes was used to evaluate the binding specificity of each compound that inhibited betaARK1 activity. The results of these analyses yielded three betaARK1-selective inhibitor leads from 11 candidates, a hit rate for selectivity of 27%. Although the IC50 values of these compounds for betaARK1 ranged from only 1.3 x 10(-4) M to 5.6 x 10(-4) M, the compounds did not inhibit PKA at concentrations up to 1.0 x 10(-3) M. Thus, the present study shows the usefulness of a rational drug design strategy in finding specific kinase inhibitors for proteins with similar drug target binding sites.