Advances in Anticoagulants

Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE)

“…The terminal cyclopropyl group, linked by an amide to the core of BCX4161, nestles in the hydrophobic cavity formed by Phe 143 , Ile 151 , and Leu 41 (S′ sites) (Figure b). The poor oral bioavailability of BCX4161, resulting from poor absorption of the inhibitor due to the highly charged benzamidine group − and poor solubility, led us to design a second-generation molecule with improved solubility and decreased charge.…”

“…Reports in the literature provide examples where replacing the highly charged and basic benzamidine substituent of serine protease inhibitors with a less basic moiety may improve their pharmacokinetic (PK) profiles. − Of all the benzamidine mimics reported in the literature, benzylamine is the closest in structure and basicity (p K a = 8.8) when compared to benzamidine (p K a = 10.5). Work reported by Pinto and co-workers ,, has described and validated the use of pyrazole-benzylamine as a successful replacement for the benzamidine moiety in a drug candidate that was a Factor (F) Xa serine protease inhibitor.…”

“…A comparison of the physical/chemical properties and PK profiles for BCX4161 and BCX7353 is provided in Table . Previous work has shown that although highly basic benzamidine compounds can be effective inhibitors of FXa serine proteases, these molecules tend to have poor oral bioavailability. , In our development of PKal inhibitors, we find the benzylamine replacement in BCX7353 leads to decreased basicity and greatly improved solubility relative to the benzamidine-containing BCX4161, with a 392-fold increase in solubility at pH 4.0 in aqueous solution at ambient temperature (47 mg/mL compared to 0.12 mg/mL, respectively) and a 7-fold increase at pH 7.0 (1.09 mg/mL compared to 0.16 mg/mL, respectively), with corresponding changes to the cLogP (3.74 compared to 2.21, respectively). The potency observed with BCX7353 is similar to that of BCX4161 with both displaying K i ’s in the picomolar range, while selectivity is improved (12 500-fold reduction in potency with trypsin relative to PKal compared to 8192-fold, respectively).…”

Anticoagulant Macromolecules

“…Heparin is a naturally occurring elevated sulfur polysaccharide, which is one of the most widely used anticoagulant macromolecules at present . It has been generally used in various aspects such as tissue regeneration, anti-inflammatory activity, maintaining protein stability, and anticoagulant coatings for biomedical devices. − However, the only source of heparin is animal tissue, which carries the burden of high production cost, large side effects, and complicated synthesis procedures.…”

Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

“…10 A number of diverse series of small molecule TF-FVIIa inhibitors have been reported to date. 11 Based on the interaction with the polar primary specificity pocket, the reported FVIIa inhibitors could be nominally divided into two categories. The first group is comprised of compounds bearing strongly basic benzamidine P1 moieties, 12a which are characterized by high TF-FVIIa inhibitory potency, but exhibit low permeability and poor oral absorbance.…”