Background
Milvexian (BMS‐986177/JNJ‐70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials.
Objectives
To evaluate in vitro properties and in vivo ...characteristics of milvexian.
Methods
In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic‐induced carotid arterial thrombosis and cuticle bleeding time (BT).
Results
Milvexian is an active‐site, reversible inhibitor of human and rabbit FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial thromboplastin time (APTT) without changing prothrombin time and potently prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for in vivo prevention and treatment of thrombosis. For prevention, milvexian 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of control. Seventy‐five minutes after milvexian administration, CBF averaged 1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and milvexian 0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; n = 6/group). The combination of milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy.
Conclusions
Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with milvexian as a promising antithrombotic therapy with a wide therapeutic window.
The selective C−H functionalization of aliphatic molecules remains a challenge in organic synthesis. While radical chain halogenation reactions provide efficient access to many halogenated molecules, ...the use of typical protocols for the selective halogenation of electron‐deficient and strained aliphatic molecules is rare. Herein, we report selective C−H chlorination and fluorination reactions promoted by an electron‐deficient manganese pentafluorophenyl porphyrin catalyst, Mn(TPFPP)Cl. This catalyst displays superior properties for the aliphatic halogenation of recalcitrant, electron‐deficient, and strained substrates with unique regio‐ and stereoselectivity. UV/Vis analysis during the course of the reaction indicated that an oxo‐MnV species is responsible for hydrogen‐atom ion. The observed stereoselectivity results from steric interactions between the bulky porphyrin ligand and the intermediate substrate radical in the halogen rebound step.
A deficiency that's a bonus: A highly electron‐deficient manganese porphyrin was found to effectively catalyze the radical halogenation of strained, electron‐deficient aliphatic substrates under mild conditions (see scheme). The bulkiness of the catalyst resulted in unique stereo‐ and regioselectivity.
A generic activation mode for asymmetric LUMO-lowering catalysis has been developed using the long-established principles of oxy-allyl cation chemistry. Here, the enantioselective conversion of ...racemic α-tosyloxy ketones to optically enriched α-indolic carbonyls has been accomplished using a new amino alcohol catalyst in the presence of electron-rich indole nucleophiles. Kinetic studies reveal that the rate-determining step in this SN1 pathway is the catalyst-mediated α-tosyloxy ketone deprotonation step to form an enantiodiscriminant oxy-allyl cation prior to the stereodefining nucleophilic addition event.
Enamines and enol ethers are versatile synthons for chemical synthesis. While several methods have been developed to access such molecules, prefunctionalized starting materials are usually required, ...and direct desaturation methods remain rare. Herein, we report direct desaturation reactions of N-protected cyclic amines and cyclic ethers using a mild I(III) oxidant, PhI(OAc)2, and an electron-deficient manganese pentafluorophenylporphyrin catalyst, Mn(TPFPP)Cl. This system displays high efficiency for α,β-desaturation of various cyclic amines and ethers. Mechanistic probes suggest that the desaturation reaction occurs via an initial α–C-H hydroxylation pathway, which serves to protect the product from overoxidation.
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa ...has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models ( Weitz, J. I. , Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7−12 ). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2′ moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa K i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
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Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for ...antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein.
A three-step synthesis of a precursor to the C11−C23 segment of (−)-dictyostatin is described. The sequence features a sonication-assisted, enantioselective double hetero Diels−Alder (HDA) reaction ...catalyzed by Jacobsen's Cr(III) Schiff base catalyst, followed by a novel, highly diastereoselective Meerwein−Ponndorf−Verley (MPV) reduction of the hydropyranone subunits under kinetic control to yield the bis(axial alcohol) 4. Generalized studies of both the HDA and MPV methodologies are also described.
In this study, a new eco-friendly process was developed for the removal of volatile organic compounds (VOC) from contaminated groundwater. The new process included two steps. The first step is a ...solvent extraction process using a high-efficiency centrifugal contactor, in which the VOC's were extracted from the groundwater using cooking oils, acting as safe and environment-friendly solvents. In the second step, the VOC's were removed from the oil by a distillation process, after which the cooking oil can be recycled for another extraction. Using five cooking oils, distribution ratios showed high affinity of the VOC's to the oil phase, indicating efficient extraction. Hydraulic tests showed that corn oil performed best in terms of ease of mixing and separation from the water. A stage efficiency test showed that high stage efficiency, in excess of 90%, can be achieved in the centrifugal contactor. Finally, a distillation test, using a wiped-film distillation unit, showed that more than 95% of the VOC can be removed from the oil under mild operating conditions. Based on these results, a proof-of-concept for the new technology was achieved.
•A new process was developed for the removal of VOC compounds from contaminated groundwater.•This is a two-steps process; solvent extraction followed by VOC removal from the oil by distillation.•High-efficiency centrifugal contactors are used in the extraction using cooking oils as solvents.•High affinity of the VOC to the oils was demonstrated, indicating efficient extraction.•Simulations and distillation tests showed that the VOC can be efficiently recovered from the oil.
The selective C−H functionalization of aliphatic molecules remains a challenge in organic synthesis. While radical chain halogenation reactions provide efficient access to many halogenated molecules, ...the use of typical protocols for the selective halogenation of electron‐deficient and strained aliphatic molecules is rare. Herein, we report selective C−H chlorination and fluorination reactions promoted by an electron‐deficient manganese pentafluorophenyl porphyrin catalyst, Mn(TPFPP)Cl. This catalyst displays superior properties for the aliphatic halogenation of recalcitrant, electron‐deficient, and strained substrates with unique regio‐ and stereoselectivity. UV/Vis analysis during the course of the reaction indicated that an oxo‐MnV species is responsible for hydrogen‐atom ion. The observed stereoselectivity results from steric interactions between the bulky porphyrin ligand and the intermediate substrate radical in the halogen rebound step.
Arm aber wirkungsvoll: Ein elektronenarmes Manganporphyrin erweist sich als effektiver Katalysator für die radikalische Halogenierung von gespannten, elektronenarmen aliphatischen Substraten unter milden Bedingungen (siehe Schema). Die sterische Überfrachtung des Katalysators führt zu einer einzigartigen Stereo‐ und Regioselektivität.
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