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FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties. Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring. In BDC rat, the absorbed dose of [3H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites. In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6, a descarbamoylated metabolite, was more prominent in rat plasma, and M9, a hydroxylated metabolite, was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey. [ABSTRACT FROM AUTHOR]

Fluorine is known to promote ortho‐C−H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho‐palladation intermediate and is then relayed to the meta position, leading to meta‐selective C−H arylation of fluoroarenes. Deuterium experiment suggests that this meta‐arylation is initiated by ortho C−H activation and the catalytic cycle is terminated by C‐2 protonation. A dual‐ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity. [ABSTRACT FROM AUTHOR]

The use of chiral transient directing groups (TDGs) is a promising approach for developing PdII‐catalyzed enantioselective C(sp3)−H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C−H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII‐catalyzed enantioselective β‐C(sp3)−H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C−H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity. [ABSTRACT FROM AUTHOR]

A general β‐C−H arylation of electron‐deficient thiophenes, pyrroles, and furans has been developed using ligand‐modulated palladium catalyst. The use of a modified norbornene is crucial for reversing the conventional α‐selectivity of these substrates. This method features good yields, high β‐selectivity, and good tolerance of functional groups. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: The cannabinoid CB1 G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptor''s three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB1 receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB1 receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB1 receptor ligands. [Copyright &y& Elsevier]

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.

γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp 3 )-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N -acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert -butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.

Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium experiment suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f , a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd II -catalyzed enantioselective C(sp 3 )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd II centers, which can result in a mixture of reactive complexes. We report a Pd II -catalyzed enantioselective β-C(sp 3 )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a redox-neutral method for nucleophilic fluorination of N -hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [ 18 F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N -hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral S N 1 substitutions under mild conditions.