Search

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.

SU5416, Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, is a cytostatic substance in development as an anti-angiogenic agent. SU5416 has several phase I and phase II metabolites including SU9838, SU6595, SU6689, 5′-hydroxy glucuronide of SU5416 and 5′-acyl glucuronide of SU5416. In order to support the preclinical studies, a liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method for simultaneous determination of SU5416 and its metabolites in rat and dog plasma was developed. This method is fast, simple, sensitive (LOQ=2.0 ng/ml), reproducible and has a wide linear range (2.0–5000 ng/ml for SU5416, 2.0–2000 ng/ml for SU6689 and 2.0–1000 ng/ml for SU9838 and SU6595). This method was applied to rat and dog plasma samples obtained from pharmacokinetic and toxicokinetic studies.

The intestinal peptide transport system has broad substrate specificities. In addition to its physiological function of absorbing di- and tripeptides resulting from the digestion of dietary proteins, this transport system also absorbs some orally administered peptidomimetic drugs, including β-lactam antibiotics, angiotensin converting enzyme inhibitors, renin inhibitors, bestatin, thrombin inhibitors, and thyrotropin-releasing hormone and its analogues. There have been several studies on the mechanism and substrate structure-affinity relationship for this transport system. Rapid progress has been made recently in studies on the molecular basis of the intestinal peptide transport system. A protein apparently involved in peptide transport has been isolated from rabbit small intestines, and genes for human intestinal peptide transporters have been cloned, sequenced and functionally expressed. This review summarizes these studies and addresses the pharmaceutical potential of the intestinal peptide transport system.

Immobilized Artificial Membranes (IAMs) are monolayers of phospholipid analogs covalently bonded to the surface of silica particles. 31P NMR and molecular dynamics (MD) simulations demonstrated that IAMs and liposome membranes exhibit similar interfacial properties. These similar interfacial properties have resulted in IAMs' being useful as a physico-chemical model of drug-membrane partitioning. IAM chromatography has been successful used to predict: (1) solute partitioning into liposome membranes; (2) drug permeability through Caco-2 cells; (3) drug intestinal absorption; (4) brain uptake of amino acids; (5) bile salt-membrane interactions; and (6) human skin permeability of steroids and alcohols. In addition, IAM chromatography has also been used to obtain hydrophobicity parameters for SAR studies.

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-β, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies. [Mol Cancer Ther 2006;5(7):1774–82]

A new solution for the hydrodynamic force on dams due to random earthquake accelerations is obtained in terms of nonstationary power spectra and mean square functions. Numerical results and special analytic solutions are obtained and presented in nondimensional forms. The earthquake acceleration is modeled by a stationary white noise with a unit step modulation function. The response spectra are narrowly banded and sharply peaked at resonant frequencies.

This paper presents a new analytic solution to the problem of predicting the change of energy as random waves propagate from deep water towards the shore lines. Some relevant results of the deterministic wave theory are first reviewed along with the classical result of Longuet-Higgins on the transformation of a continuous wave spectrum based on the concepts of the conservation of energy flux.

In this paper an approximate formulation and a closed form solution are obtained, based on an extension of the elementary formulation of Von Karman.

A numerical method is developed for the calculation of first-passage time probability of single degree-of-freedom, linear and nonlinear, dynamic oscillators excited by Gaussian white noise. The random walk model is a difference equation which governs the diffusion of the oscillators response probability in the phase plane and is a discrete analog to the continuous theory Fokker-Planck equation. First-passage is examined by considering the diffusion process when absorbing barriers are superimposed upon the phase plane. Two linear systems are studied for first-passage and compared to results from another numerical approach with good correlation. First-passage is also examined for several nonlinear systems to demonstrate its applicability. It is the study of the latter for which the technique has particular value.

The dynamic response of a one-dimensional column is investigated theoretically. The column is loaded concentrically by a compressive or tensile pulse at one end and is fixed at the other. The material property of the column is represented by an idealized elastic-viscous-plastic law. For such a column, the partial differential equations governing one-dimensional motion are formulated. Since the idealized system of partial differential equations is linear and hyperbolic, it is readily transformed into a system of ordinary differential equations that are solved numerically by a digital computer for the appropriate boundary and initial conditions. The result of the response computation is presented graphically in a nondimensional form, as maximum and minimum strain in the column for load pulses of various durations. A comparison with the linear elastic solution is made. Finally, it is demonstrated that the obtained result may be used to design steel and reinforced concrete columns for dynamic loads.