Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors.

Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.

Vasopressor stewardship: a case report and lesson shared.

A case report, focused on vasopressor use and presented in this article, is likely to resonate with many critical care nurses. In this article the authors describe opportunities to enhance safety with vasopressor therapy. Specifically, the goal of improving communication among physicians, nurses, and pharmacists around desired endpoints for vasopressor therapy, triggers for reassessment of the therapeutic strategy and cause of the patient's shock was identified as an area for improvement. A form piloted within an organization for use during multidisciplinary rounds and key findings is shared. Vasopressors constitute the mainstay of therapy for nearly every hemodynamically unstable patient in critical care. It is hoped that the lessons and information shared help empower critical care nurses to facilitate vasopressor stewardship within their facilities and, ultimately, enhance patient safety.

Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.

Potent P2Y1 urea antagonists bearing various cyclic amine scaffolds.

A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.

New azole antagonists with high affinity for the P2Y(1) receptor.

Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.

Novel tricyclic inhibitors of IkappaB kinase.

The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.

Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor.

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.

Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia.

PURPOSE: To assess the effectiveness of low-dose salmon oil for the treatment of highly active antiretroviral therapy (HAART)-induced dyslipidemia in HIV-infected patients. METHOD: Randomized, open-label, parallel and crossover, multicenter study. Patients received 1 g salmon oil tid for 24 weeks (SO-24) or no additional treatment for 12 weeks and salmon oil for weeks 12 to 24 (CT-SO). The primary outcome measure was the change in triglyceride (TG) levels. RESULTS: Fifty-eight patients completed the study (26 in SO-24; 32 in CT-SO). After 12 weeks, the SO-24 group experienced a mean TG reduction of 1.1 mmol/L, compared to an increase of 0.3 mmol/L for the CT-SO group (p = .040). When CT-SO patients were crossed over to salmon oil treatment, mean TG decreased by 0.7 mmol/L (p = .052). Concomitant use of fibrates, statins, or both were reported by 16 (27.6%), 10 (17.2%), and 8 (13.8%), respectively. Multivariate analysis showed that salmon oil produced a significant decrease in TG levels independent of other lipid-lowering medications (p = .022). There were 26 predominately mild treatment-emergent (antiretroviral or salmon oil) nonserious adverse events reported by 22 (33.3%) patients. CONCLUSION: Low-dose salmon oil (3 g/day) is effective and well-tolerated in reducing TG levels in HIV-infected patients receiving HAART.

Randomized controlled trial of once-daily tenofovir, lamivudine, and lopinavir/ritonavir versus remaining on the same regimen in virologically suppressed HIV-infected patients on their first PI-containing HAART regimen.

PURPOSE: To assess the effects of switching to once-daily (QD) lopinavir/ritonavir (LPV/r)-based combination therapy in HIV-infected patients who are virologically suppressed (HIV viral load <50 copies/mL) on their first protease inhibitor (PI)-containing regimen. METHOD: In this 48-week, prospective, open-label, randomized study, patients were either switched to once-daily LPV/r, tenofovir (TDF), and lamivudine (3TC) (QD arm) or remained on their existing regimen (control arm). The primary endpoint of the study was the proportion of patients maintaining virologic suppression following 48 weeks of treatment. RESULTS: Fifty and 22 patients were randomized to the QD and control arms, respectively. At week 48, there was no significant difference in virological suppression between the QD and control arms using intent-to-treat (missing = failure) analysis (p = .44). There was no significant difference in discontinuation rates between the two arms (p = .66). Significantly more patients randomized to the QD arm reported gastrointestinal adverse events compared with the control arm (p = .009). There were no study drug-related serious adverse events. CONCLUSION: For patients who are already virologically suppressed on their first PI-containing regimen, switching to a QD regimen of TDF+3TC+LPV/r resulted in similar rates of virologic suppression when compared with staying on existing therapy.

Benzyl amide-ketoacid inhibitors of HIV-integrase.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. Previous reports have demonstrated that the diketoacid-based chemotype is a useful starting point for the design of inhibitors of this enzyme. In this study, one of the ketone groups is replaced by a benzylamide resulting in a new potent chemotype. A preliminary SAR study is carried out to investigate the substitution requirements on the phenyl ring and methylene group of the benzylamide.

Synthesis and structure-activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-beta inhibitors.

The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.

Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors.

We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.

Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial.

BACKGROUND: Famciclovir, the oral prodrug of penciclovir, is effective for the treatment of recurrent genital herpes. This randomized, clinic-initiated, double-blind trial compared the therapeutic efficacy and safety of treatment with famciclovir at dosages of 125 mg, 250 mg, and 500 mg twice daily for 5 days with placebo in immunocompetent adults with a recurrent episode of genital herpes. METHODS: Efficacy and tolerability were assessed in 308 patients with lesions present for no more than 6.5 h at the time of the first dose. Two assessments per day were performed to increase the precision of the determination of study end points. RESULTS: All doses of famciclovir were significantly more effective than placebo in reducing the time to cessation of viral shedding, complete lesion healing, and loss of all lesion-associated symptoms, particularly lesion tenderness, pain, and itching. Patients receiving treatment with famciclovir were significantly less likely to experience new lesions than were patients receiving placebo. All doses of famciclovir were tolerated as well as placebo was. There was no difference in efficacy or tolerability among the different doses of famciclovir; the lowest effective dose was 125 mg twice per day. CONCLUSIONS: In immunocompetent adults with recurrent genital herpes, a 5-day course of famciclovir at a dosage of 125 mg, 250 mg, or 500 mg twice per day was significantly more effective than was placebo in reducing the duration of viral shedding and symptoms and in accelerating lesion healing. These results support the use of treatment with famciclovir at a dosage of 125 mg for 5 days as an effective, well-tolerated treatment for episodes of recurrent genital herpes.

Biaryl isoxazolinone antibacterial agents.

In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.

Discovery of a fluoroindolo[2,3-a]carbazole clinical candidate with broad spectrum antitumor activity in preclinical tumor models superior to the marketed oncology drug, CPT-11.

A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.

(S,E)-N-[1-(3-heteroarylphenyl)ethyl]-3-(2-fluorophenyl)acrylamides: synthesis and KCNQ2 potassium channel opener activity.

Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.

Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials.

A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.

Design and synthesis of a fluoroindolocarbazole series as selective topoisomerase I active agents. Discovery of water-soluble 3,9-difluoro-12,13-dihydro-13-[6-amino-beta-D-glucopyranosyl]-5H,13H-benzo[b]- thienyl[2,3-a]pyrrolo[3,4-c]carbazole- 5,7(6H)-dione (BMS-251873) with curative antitumor activity against prostate carcinoma xenograft tumor model.

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.