A new class of nonpeptidic inhibitors of the Zn II -dependent metalloprotease neprilysin with IC 50 values in the nanomolar activity range (0.034 ± 0.30 mm) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo [4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable p-p stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn II ion and an aryl residue to occupy the hydrophobic S1' pocket, but lack a substituent for binding in the S2' pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds ()-1, ()-2, ()-25, and ()-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors ()-2 and ()-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core (()-1 and ()-25) ( Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with ()-2 at 2.25-resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn II ion, and the benzyl residue occupies the S1' pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes p-p stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazopyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1' pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.1. Introduction. ± In the preceding paper [1], we described a new class of inhibitors of the metalloprotease neprilysin with a central 1H-imidazole platform, featuring IC 50 values (IC 50 : concentration of inhibitor at which 50% V max is observed) in the low micromolar range. The de novo design of these compounds was based on the X-ray crystal structure of NEP complexed with phosphoramidon (Protein Data Bank (PDB) file name 1DMT) [2]. For the design of the second-generation inhibitors, we reverted to an unpublished X-ray crystal structure [3] of NEP complexed with the inhibitor thiorphan [4]. During the analysis, we carefully compared the active sites of the two

Structure-activity relationships for new members of a class of nonpeptidic, low-molecular-weight inhibitors of thrombin, a key serine protease in the blood coagulation cascade, are described. These compounds, which originate from X-ray-structure-based design, feature a conformationally rigid, bi-or tricyclic core from which side chains diverge into the four major binding pockets (distal D, proximal P, recognition or specificity S1, and oxyanion hole O) at the thrombin active site (Fig.

Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a Zn II -dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((AE)-1, (AE)-43, (AE)-45, and (AE)-46; Table) were designed, based on the X-ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H-bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the Zn II ion and two aromatic residues to bind into the hydrophobic S1' and S2' pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1 ± 4 and 5 ± 8), with the second one involving a double directed ortho-metallation of the imidazole platform and a Stille cross-coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (AE)-1, (AE)-43, (AE)-45, and (AE)-46 all exhibit IC 50 values in the single-digit micromolar activity range (2 ± 4 mm, Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.

Using X‐ray structure‐based de novo design, a new class of inhibitors of the zinc‐dependent endopeptidase Neprilysin has been developed that feature binding affinities (IC50 values) in the upper nanomolar range. The imidazole moieties of the central benzimidazole or imidazo[4,5‐c]pyridine (see picture) scaffolds act as efficient peptide‐bond isosters.

As vixotrigine (1) entered a later clinical phase for trigeminal neuralgia (ZakrzewskaJ. M. Zakrzewska, J. M. Lancet Neurol.201716291300), the development of a sustainable late-stage process was required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches (this is the expected commercial formulation). In this article, we describe how the process was streamlined from the early supply route (GiblinG. Giblin, G. 10.1021/acs.oprd.0c00382Org. Process Res. Dev.2020) and a comprehensive control strategy was established. Process improvements included improving safety and scalability for a temperature-sensitive Grignard reaction, simplifying unit operations, removal of heterogenous conditions, and route redesign to afford a high yielding, one-pot sequential alkylation and amidation. Improvement in the salt formation step, combined with wet milling, resulted in improved particle properties with enhanced flow properties of the final active pharmaceutical ingredient. The process mass intensity was improved 65% while maintaining drug substance purity at more than 99.8%. This new process has been scaled up to generate metric ton quantities of drug substance.

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