Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Rapid Analysis of Cell-Nanoparticle Interactions using Single-Cell Raman Trapping Microscopy.

Iron oxide nanoparticles have been used in preclinical studies to label stem cells for non-invasive tracking and homing. The search continues for novel particle candidates that are suitable for clinical applications. Since standard analyses to investigate cell-particle interactions and safety are labor-intensive, an efficient procedure is required to guide future particle development and to exclude adverse health effects. The application of combined Raman trapping microscopy with fluidic chips is reported for the analysis of single cells labeled with different types of aminated iron oxide particles. Multivariate data analysis revealed Raman signal differences that could be clearly assigned to cell-particle interactions and cytotoxicity, respectively. A validation dataset verified that more than 95 % of the spectra were correctly classified. Thus, our approach enables rapid discrimination of non-hazardous from cytotoxic nanoparticles as a prerequisite for safe clinical applications.

The Ti-BINOLate-catalyzed, enantioselective ring-opening of meso-aziridines with amines.

The titanium-BINOLate-catalyzed, highly enantioselective ring-opening reaction of meso-aziridines has been developed which furnishes trans-1,2-diamines in typically good yields and excellent enantioselectivities. N-Aryl aziridines attached to a 5- or 6-membered carbocyclic ring are among the best substrates for this process providing the products in up to >99% ee. The chiral catalyst is easily prepared in situ from commercially available components and does not require any laborious ligand synthesis. Structural investigations into the catalyst composition reveal an oligomeric structure of the active Ti-complex.

One-point binding ligands for asymmetric gold catalysis: phosphoramidites with a TADDOL-related but acyclic backbone.

Readily available phosphoramidites incorporating TADDOL-related diols with an acyclic backbone turned out to be excellent ligands for asymmetric gold catalysis, allowing a number of mechanistically different transformations to be performed with good to outstanding enantioselectivities. This includes [2 + 2] and [4 + 2] cycloadditions of ene-allenes, cycloisomerizations of enynes, hydroarylation reactions with formation of indolines, as well as intramolecular hydroaminations and hydroalkoxylations of allenes. Their preparative relevance is underscored by an application to an efficient synthesis of the antidepressive drug candidate (-)-GSK 1360707. The distinctive design element of the new ligands is their acyclic dimethyl ether backbone in lieu of the (isopropylidene) acetal moiety characteristic for traditional TADDOL's. Crystallographic data in combination with computational studies allow the efficiency of the gold complexes endowed with such one-point binding ligands to be rationalized.

Titanium binolate catalyzed aminolysis of meso aziridines: a highly enantioselective and direct access to 1,2-diamines.

It's as simple as that: An in situ prepared chiral catalyst from the commercially available compounds Ti(OiPr)(4) and (R)-binol catalyzes the highly enantioselective ring-opening of meso-aziridines 1 with anilines 2 and furnishes valuable chiral 1,2-diamines 3 in high yields and up to 99 % ee.(R)-binol=(R)-2,2'-dihydroxy-1,1'-binaphthyl.