Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.

An Evaluation of Permit L Local Anesthesia within Dental Hygiene Practice in Massachusetts.

PURPOSE: The purpose of this descriptive study was to assess data pertinent to the Permit L local anesthesia license among practicing dental hygienists in Massachusetts, providing an overview of characteristics, practice behaviors, barriers for obtaining the permit and self-perceived competency. METHODS: A convenience sample of dental hygienists (n=6,167) identified through a publically available data base were invited to participate in a web-based survey. The survey consisted of demographic and Permit L specific questions. Items regarding opinions were rated using a 5-point Likert scale while frequencies and percentiles were used to evaluate demographics and practice-based information. Spearman's Rank correlation was performed to determine association between variables. RESULTS: A 10% (n=615) response rate was attained with (n=245) non-Permit L holders and (n=370) Permit L holders. Respondents reported significant differences in demographics and opinions between non-Permit L holders and Permit L holders (p<0.01) and between those certified through continuing education or curriculum based programs (p<0.01). Significant relationships were found in demographics (p<0.01) and practice (p<0.05) items in relation to the length of time the Permit L has been held. Themes from the data and comments indicate multiple factors influencing obtaining or not obtaining the Permit L. CONCLUSION: The results of this study provide an overview of Permit L local anesthesia administration that is generally comparable to previous studies and offers new insights into why some Massachusetts dental hygienists choose not to pursue certification. This study highlights the potential to increase the prevalence of the Permit L, address barriers to pursuing the Permit L, and further evaluate self-perceived barriers.

Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection.

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.

Electrical acustimulation of the wrist for chronic neck pain: a randomized, sham-controlled trial using a wrist-ankle acustimulation device.

OBJECTIVES: Chronic neck pain is a common problem and is treated using a variety of conservative treatments. This single-blind, randomized, sham-controlled trial investigated the value of adding electrical stimulation of acupuncture points on the wrist to a standardized program of neck exercises for chronic neck pain. METHODS: At initial recruitment 60 patients were randomly assigned to receive either active or sham electrical stimulation of acupuncture points on the wrist in addition to standardized neck exercise. Active or sham wrist acustimulation was given for 30 minutes 2 times/wk over a period of 4 weeks. A 30 minutes program of standardized neck exercises was also performed simultaneously. RESULTS: Forty-nine patients completed the study (22 active, 27 sham). Statistically significant improvements were found for acustimulation when compared with sham at immediate posttreatment and 1-month posttreatment for Numerical Rating Scale, Northwick Park Neck Pain Questionnaire and Pain Self-Efficacy Questionnaire. In active and sham electrical stimulation group 38.9% and 8.3% of patients reported a reduction of Numerical Rating Scale > 50% at 1-month posttreatment follow-up, respectively. All patients tolerated acustimulation and no adverse effects were reported. DISCUSSION: Electrical acustimulation of the wrist administered as two, 30 minutes sessions /wk added value to standardized neck exercise for chronic neck pain. A 4-week course of treatment produced effects lasting 1-month posttreatment.