Multinuclear magnetic resonance study of sterically crowded stannylphosphines and stannylamines : stereochemical influences on chemical shielding and spin-spin couplings

Multinuclear (1H, 15N, 29Si, 31P, 119Sn) NMR data of sterically crowded acyclic stannylphosphines tBu3SnPHY (Y = H, SnMe3, SntBu3, SiMe3; 1-3, 10), (tBu2RSn)2PH (R = Me, Cl; 4, 5), tBu3SnPY2 (Y = SnMe3, SiMe3; 6, 11), PH(SntBu2PHSntBu3)2 (7), SntBu2(PY2)2 (Y = H, SiMe3, PHSntBu3; 8, 9, 12), cyclic stannylphosphines (tBu2SnPY)n (n = 2, Y = H, C3H6Cl, tBu, SnMe3; 13-16; n = 3, Y = H; 18), (Me2SnPSntBu3)2 (17), and stannylamines tBu3SnNHY (Y = H, SnMe3, SntBu3; 19-21) were obtained by various 1D- and 2D-techniques. 31P- and 15N-shieldings may be explained qualitatively in terms of two counteracting influences, viz electronegativity differences and steric requirements of the substituents. In a similar manner, the trends in one-bond coupling 1KSnP and 1KSnM may be rationalized using a simple model based on the deformation of bond angles by sterically demanding substituents. The signs of long-range couplings 2KSnPH and 1KPSnCCH could be determined, which may be useful for future structural studies. Temperature-dependent effects in the spectra of 13, 18 allow conclusions about the conformational dynamics of the molecules

MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate <b>15</b> (MK-5172), which is active against genotype 1–3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species