Control of Mechanical Stability of Hollow Silica Particles, and Its Measurement by Mercury Intrusion Porosimetry.

Hollow silica particles (HSPs) have become the focus of interest in many laboratories recently, because of their versatility, stemming from the ability to control their size and shape, as well as surface functionalization. Determining the mechanical stability of hollow particles is essential for their use, both in applications in which they need to retain their structure, as well as those in which they need to break down. We have synthesized a series of HSPs (inner diameter of 231 nm) with increasing wall thickness (7-25 nm), using a template approach. Their mechanical stability was measured using mercury intrusion porosimetry (MIP), which represents the novel application of the technique for these materials. The samples with complete shells break at progressively higher pressures, and samples with wall thickness ≥21 nm remain stable to the highest pressure applied (414 MPa). Other characterization methods, namely microscopy, gas adsorption, and small-angle X-ray scattering, shed light on the size parameters of the particles, as well as the porosity of the silica walls. By varying the amount of silica precursor used in the template coating step, we were able to produce hollow silicas with variable stability, thereby allowing for control of their mechanical properties.

Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.

Phenyltriazolinones as potent factor Xa inhibitors.

We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.

The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2'-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.

Synthesis and biological evaluation of nonpeptide integrin antagonists containing spirocyclic scaffolds.

Analogues of isoxazoline alpha(v)beta(3) antagonist 1 designed to further restrict the four carbon alkyl tether were prepared by incorporating two spirocyclic scaffolds, 1-oxa-2-azaspiro[4,5]dec-2-ene and 1-oxa-2,7-diazaspiro[4,4]non-2-ene. Additional optimization provided potent antagonists of both alpha(v)beta(3) and alpha(5)beta(1) which are selective over GPIIb/IIIa.

Nonbenzamidine tetrazole derivatives as factor Xa inhibitors.

Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.