The blood coagulation cascade represents an attractive target for antithrombotic drug development, and recent studies have attempted to identify oral anticoagulants with inhibitory activity for enzymes in this cascade, with particular attention focused on thrombin and factor Xa (fXa) as typical targets. We previously described the discovery of the orally active fXa inhibitor darexaban (1) and reported a unique profile that compound 1 rapidly transformed into glucuronide YM-222714 (2) after oral administration. Here, we propose a novel strategy towards the discovery of an orally active anticoagulant that is based on the bioconversion of a non-amidine inhibitor into the corresponding conjugate to boost ex vivo anticoagulant activity via an increase in hydrophilicity. Computational molecular modeling was utilized to select a template scaffold and design a substitution point to install a potential functional group for conjugation. This strategy led to the identification of the phenol-derived fXa inhibitor ASP8102 (14), which demonstrated highly potent anticoagulant activity after biotransformation into the corresponding glucuronide (16) via oral dosing.
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http://dx.doi.org/10.1016/j.bmc.2014.09.059 | DOI Listing |
Cureus
December 2024
Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, JPN.
Left ventricular (LV) thrombus is a serious complication of myocardial infarction (MI) that can lead to a fetal systemic embolism. Although coronary artery bypass graft surgery (CABG) after MI is widely performed, to our knowledge, there are no reports of LV thrombus in the early postoperative period. Here, we report a rare case of a 70-year-old man who underwent off-pump coronary artery bypass grafting (OPCAB) for unstable angina pectoris with reduced left ventricular ejection fraction (LVEF).
View Article and Find Full Text PDFCureus
December 2024
Medicine and Surgery, Khyber Medical University, Peshawar, PAK.
Background: The management of thromboembolic risk and the necessity for timely hemorrhage control make anticoagulant-related gastrointestinal (GI) bleeding clinically challenging.
Objective: This study aimed to evaluate clinical outcomes (such as bleeding control and mortality) and the effectiveness of anticoagulation reversal techniques in patients with anticoagulant-related GI bleeding in emergency settings.
Methodology: This prospective, observational study conducted at Lady Reading Hospital, Peshawar, from January to December 2023, included patients aged 18 or older with GI bleeding on warfarin or direct oral anticoagulants (DOACs).
Zhongguo Shi Yan Xue Ye Xue Za Zhi
December 2024
Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, NHC Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology, Suzhou 215006, Jiangsu Province, China.
Objective: To study the molecular mechanism of functional defect of protein C (PC) caused by point mutations of human protein C gene ( ) N355S , G392E and T314A.
Methods: The wild-type and mutant plasmids (PC, PC, PC, PC) of gene were constructed and transiently transfected into HEK293 cells. The expression of mutant proteins in vitro were tested.
Mymensingh Med J
January 2025
Dr Khondokar Shamim Shahriar Ziban Rushel, Assistant Professor, Department of Cardiac Surgery, National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh; E-mail:
Heparin is an anticoagulant used invariably in all cardiac surgery. Heparin dosing and its reversal were determined by monitoring activated clotting time (ACT). Intermittent heparin dosing after initial bolus dose is widely practiced to maintain ACT level 200-300 seconds in Off-pump coronary artery bypass surgery (OPCAB).
View Article and Find Full Text PDFNeurol Neurochir Pol
December 2024
Department of Thromboembolic Diseases, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.
Clinical Rationale For Study: We have reported that intracerebral haemorrhage (ICH) of unknown cause at a young age is associated with lower prothrombin and factor VII and higher antithrombin activity, along with the formation of looser fibrin networks displaying enhanced lysability. Patients with mild-to-moderate bleeding of unknown cause have elevated levels of free plasma tissue factor pathway inhibitor alpha (fTFPIα), inhibiting the tissue factor-factor VII complex and prothrombinase.
Aim Of Study: We hypothesised that patients with an intracerebral haemorrhage (ICH) of unknown cause may also exhibit higher fTFPIα.
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