Rational Design, Synthesis, and Structure−Activity Relationships of Novel Factor Xa Inhibitors:  (2-Substituted-4-amidinophenyl)pyruvic and -propionic Acids

Abstract

An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…Compound 40 (AXC1578; fXa K i 5 220 nM, fIIa K i 5 710 mM) was identified as a lead compound. 126 Optimization resulted in a series of pyruvic acids, as exemplified by 41 (fXa K i 5 20 nM, fIIa K i 5 53 mM, EC 2 Â PT 5 200 nM). It also showed an oral bioavailability of 12% and threefold ex vivo PT prolongation in cynomolgus monkeys after an oral dose of 10 mg/kg.…”

Syntheses of Benzo[b]furan-6-carbonitrile and 6-Cyanobenzo[b]furan-2-boronic Acid Pinacol Ester

“…Before optimizing this reaction, we wanted to unambiguously assign the regiochemistry of the product. The NMR spectrum of 3-hydroxy-4-iodobenzonitrile ( 5 ) matched literature precedent; [10] however, that synthesis also relied upon an iodination reaction that could have provided multiple products. We were, unfortunately, unable to validate the structure using HMBC/HSQC because of overlapping resonances in the 13 C spectrum.…”

“…Our initial efforts at producing 2-iodo-5-cyanophenol ( 5 ) using traditional methodologies (direct mono-iodination with ICl in acetic acid, [10] or with iodine in either aqueous sodium acetate [11] or aqueous ammonia [12]) were hampered by low yields and/or mixtures of isomers; we did not attempt analogous reactions using common thallium salt procedures [13] because of the inherent toxicity concerns about working with this heavy metal.…”

Application of Molecular Modeling to Development of New Factor Xa Inhibitors

“…The binding site is divided into 4 pockets: S1, S2, S3 (S1- β in some works), and S4 [ 21 – 23 ]. The respective moieties of inhibitors are designated as Р1, Р2, Р3, and Р4 depending on the pocket of the enzyme binding site where the moiety is located.…”