Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

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 Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

Milvexian, an orally bioavailable, small-molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits.

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.

Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase.

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.

Selective C-H Halogenation with a Highly Fluorinated Manganese Porphyrin.

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 abstraction. The observed stereoselectivity results from steric interactions between the bulky porphyrin ligand and the intermediate substrate radical in the halogen rebound step.

Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode.

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 S(N)1 pathway is the catalyst-mediated α-tosyloxy ketone deprotonation step to form an enantiodiscriminant oxy-allyl cation prior to the stereodefining nucleophilic addition event.

A two-directional approach to a (-)-dictyostatin C11-C23 segment: development of a highly diastereoselective, kinetically-controlled Meerwein-Ponndorf-Verley reduction.

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.