Biotransformation of the Novel Myeloperoxidase Inhibitor AZD4831 in Preclinical Species and Humans.

We report herein an in-depth analysis of the metabolism of the novel myeloperoxidase inhibitor AZD4831 (()-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-]pyrimidin-4(5)-one) in animals and human. Quantitative and qualitative metabolite profiling were performed on samples collected from mass balance studies in rats and humans. Exposure of circulating human metabolites with comparable levels in animal species used in safety assessment were also included.

Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.

Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models.

Identification and analyses of inhibitors targeting apolipoprotein(a) kringle domains KIV-7, KIV-10, and KV provide insight into kringle domain function.

Increased plasma concentrations of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular disease. Lp(a) is composed of apolipoprotein(a) (apo(a)) covalently bound to apolipoprotein B of low-density lipoprotein (LDL). Many of apo(a)'s potential pathological properties, such as inhibition of plasmin generation, have been attributed to its main structural domains, the kringles, and have been proposed to be mediated by their lysine-binding sites.

Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents.

Atrial fibrillation (AF) is a major cause of stroke, heart failure, sudden death and cardiovascular morbidity. The Kv1.5 potassium channel conducts the IKur current and has been demonstrated to be predominantly expressed in atrial versus ventricular tissue.

Direct Synthesis of N-Alkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of N-Alkyl Aryl Imino Esters.

The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.

Structural and functional characterization of a specific antidote for ticagrelor.

Ticagrelor is a direct-acting reversibly binding P2Y12 antagonist and is widely used as an antiplatelet therapy for the prevention of cardiovascular events in acute coronary syndrome patients. However, antiplatelet therapy can be associated with an increased risk of bleeding. Here, we present data on the identification and the in vitro and in vivo pharmacology of an antigen-binding fragment (Fab) antidote for ticagrelor.

Optimization of ketone-based P2Y(12) receptor antagonists as antithrombotic agents: pharmacodynamics and receptor kinetics considerations.

Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo.

Lead optimization of ethyl 6-aminonicotinate acyl sulfonamides as antagonists of the P2Y12 receptor. separation of the antithrombotic effect and bleeding for candidate drug AZD1283.

Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines.

Modular synthesis of ChiraClick ligands: a library of P-chirogenic phosphines.

A library of novel and diverse P-chirogenic phosphine ligands containing a triazole moiety (ChiraClick ligands) were prepared in high yield in a modular fashion that allows for variation of both the phosphine and the triazole structure, as well as giving access to the two enantiomers of the ligand.