The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

Purpose: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL).Experimental Design: Patients !18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after !1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the doseescalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics.Results: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19-75) years, median number of prior systemic therapies 6 (range, 3-14).

Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted. Clinical Trials Registration.NCT01009814.

Clinical depression, diagnosed in 5-15% of women during pregnancy, increases the risk of negative pregnancy outcomes including an increased incidence of low birth weight newborns and preterm delivery. Fluoxetine, a selective serotonin reuptake inhibitor, is often prescribed to treat depression due to its efficacy, high margin of safety, and mild side effects. However, fluoxetine initially increases plasma serotonin concentration, and serotonin causes uterine vasoconstriction in sheep, which could result in fetal hypoxemia. To assess fetal fluoxetine effects, late-gestation pregnant sheep were surgically prepared for the measurement of blood gases, heart rate, blood pressure, and uterine artery blood flow (n ϭ 29). Ewes received a 70-mg bolus i.v. infusion of fluoxetine over 2 min in 10 mL of sterile water followed by continuous infusion at a rate of 100 g/min for 8 d (n ϭ 14), or continuous infusion of sterile water (n ϭ 15). Transient decreases in uterine artery blood flow, fetal PO 2 , and oxygen saturation were observed within the first 15 min after fluoxetine exposure, which did not return to normal values by 24 h. Fetal pH decreased and PCO 2 increased over the first 4 h with a return to normal by 24 h. However, there were no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between the control and fluoxetine group over the rest of the 8-d infusion period. Thus, fluoxetine exposure during pregnancy has transient effects on fetal status that may be of developmental consequence if they occur repetitively. Depression occurs in 5-15% of pregnant women, and an additional 10 -15% of women experience postpartum depression (1). A study of general practitioner records in the United Kingdom from 1991 to 1996 showed that FX is the most prescribed SSRI (2). The SSRIs have fewer side effects than tricyclic antidepressants and monoamine oxidase inhibitors and thus are frequently prescribed during pregnancy (3). First trimester in utero exposure to FX does not result in teratogenic effects in humans (4, 5), whereas third trimester exposure has been reported to increase the incidence of preterm delivery, admission to special care nursery, poor neonatal adaptation, and to decrease birth weight (6, 7). However, other studies have found no difference in birth weight, perinatal complications, or neurobehavioral development (8, 9).Chronic FX treatment enhances serotonin neurotransmission by inhibiting serotonin reuptake by the serotonin transporter. In addition, presynaptic inhibitory 5HT 1A and 5HT 1D/1B receptors are desensitized (9). Serotonin causes contraction of the human and sheep umbilical artery (10, 11). Injections of serotonin into the uterine artery in pregnant and nonpregnant sheep results in dose-dependent decreases in UABF ranging from 20% to 50% at doses of 1-10 g (12). Whether FX interacts directly with serotonin receptors or through changes in plasma levels of serotonin, a decrease in UABF, either chronic or repeated, may be a mechanism for the possible negative effects of ...