The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice.

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks.

Analysis of the nonclinical telemetered ECG: impact of logging rate and RR bin width in the dog and cynomolgus monkey.

Introduction: Species-dependent ECG differences may affect QT interval analysis. Among these are the range of QT and RR values, heart rate variability, and respiratory sinus arrhythmia (SA). Importantly, the effects of data logging rates and RR bin width (BW) on QT analysis have not been characterized in dogs and nonhuman primates.

Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug.

17alpha-Ethinylestradiol (EE) is widely used as the estrogenic component of oral contraceptives (OC). In vitro and in vivo metabolism studies indicate that EE is extensively metabolised, primarily via intestinal sulfation and hepatic oxidation, glucuronidation and sulfation. Cytochrome P450 (CYP)3A4-mediated EE 2-hydroxylation is the major pathway of oxidative metabolism of EE.

Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies.

Background: Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors.

Materials And Methods: This study examined aripiprazole's interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties.

High-throughput quantitation of nefazodone and its metabolites in human plasma by high flow direct-injection LC-MS/MS.

A rapid, selective and sensitive high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method coupled with high flow direct-injection on-line extraction has been developed and validated for the simultaneous quantitation of nefazodone and its three active metabolites, hydroxynefazodone, triazole-dione (BMS-180492) and m-chlorophyenylpiperazine (mCPP) in human plasma. The method utilized d7-nefazodone, d7-hydroxynefazodone, d4-BMS-180492 and d4-mCPP as internal standards (IS). The plasma samples were injected into the LC-MS/MS system after simply adding the internal standard solution and centrifuging.

Is exogenous tissue plasminogen activator necessary for antithrombotic efficacy of an inhibitor of thrombin activatable fibrinolysis inhibitor (TAFI) in rats?

Introduction: TAFI indirectly reduces the action of tPA on plasminogen. Whether exogenous tPA is necessary for TAFI inhibitor efficacy is unclear. Potato carboxypeptidase inhibitor (PCI), a TAFI inhibitor, has shown variable tPA dependence in rat models of arteriovenous shunt thrombosis (required) and microthrombosis (not required).

Structure-dependent response of a chemiluminescence nitrogen detector for organic compounds with adjacent nitrogen atoms connected by a single bond.

High-throughput screening (HTS) of chemical libraries is indispensable for drug discovery research. However, the HTS data quality for lead discovery, lead optimization, and quantitative structure activity relationship studies has been severely compromised due to the uncertain compound concentrations in screening plates. In order to address this issue, we compared various high-throughput technologies for quantification of compounds in microtiter plate format without the need for authentic compounds as standards and identified the chemiluminescence nitrogen detector (CLND) as the method of choice at the present time.

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).

Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.

A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE.

Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.

Novel 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase.

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.

Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold.

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.

Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.

Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively.

Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues.

The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.

Safety assessment of drug metabolites: Characterization of chemically stable metabolites.

Drug molecules are typically subjected to a variety of biotransformation reactions, and the metabolites formed through these reactions must be considered when conducting safety testing programs for new chemical entities. Metabolites that are chemically stable sometimes have pharmacological activity profiles similar to those of the parent compound but rarely have potent activity against off-target receptors that is unique relative to the parent profile. This fact argues for the thorough testing of drug metabolites for their pharmacological activity.

Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.

A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.

Pharmacokinetics of muraglitazar (BMS-298585), a dual peroxisome proliferator-activated receptors (PPAR) alpha and gamma activator, in mice, rats, dogs, and monkeys.

The pharmacokinetic parameters of muraglitazar, a novel dual-activator of the peroxisome proliferator-activated receptors (PPAR) alpha and gamma, were determined in mice, rats, dogs, and monkeys after intravenous and oral administration. In the mouse, rat, and monkey the absolute oral bioavailability of muraglitazar ranged from 64 to 88%, and in the dog oral bioavailability was approximately 18%. The systemic clearance values of muraglitazar in the mouse, rat, dog, and cynomolgus monkey were 1.

Cyclopentanone ring-cleaved pleuromutilin derivatives.

Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents.

2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.

2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds.

Entecavir resistance is rare in nucleoside naïve patients with hepatitis B.

Comprehensive monitoring of genotypic and phenotypic antiviral resistance was performed on 673 entecavir (ETV)-treated nucleoside naïve hepatitis B virus (HBV) patients. ETV reduced HBV DNA levels to undetectable by PCR (<300 copies/mL, <57 IU/mL) in 91% of hepatitis B e antigen (HBeAg)-positive and -negative patients by Week 96. Thirteen percent (n = 88) of the comparator lamivudine (LVD)-treated patients experienced a virologic rebound (> or =1 log increase from nadir by PCR) in the first year, with 74% of these having LVD resistance (LVDr) substitutions evident.

Improvement of sordarin production through process optimization: combining traditional approaches with DOE.

BMS-353645, also known as sordarin, was of interest based on its activity against pathogenic fungi. The objective of these studies was to provide high quality starting substrate for chemical modification aimed at further improving biological activity, with particular interest in the inhibition of Aspergillus. In the work presented here, Design of Experiments, or DOE, was successfully combined with traditional approaches to significantly improve sordarin yields in fermentation flasks.

A novel method to simulate the hydrophobic effect and its application to the ranking of host/guest complexes.

Solvent entropy change is a major factor in driving the association of hydrophobic species in aqueous solutions. We have developed a novel methodology which simulates the solvation of hydrophobic surfaces by water. A system of virtual solvent particles surrounding the solute governed by arbitrarily determined rules provides a means to estimate the degree of order (Q) imposed by such solvation.

Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology.

Muraglitazar is an alpha/gamma-dual peroxisome proliferator-activated receptor (PPAR) agonist. This study evaluated the single- and multiple-dose oral toxicokinetics of muraglitazar in rats at doses of 3, 30 and 300 mg/kg/day. In total, 15 rats/gender/dose group received muraglitazar every day for 1 month.

Core exploration in optimization of chemokine receptor CCR4 antagonists.

The design, synthesis, and SAR studies of 'core' variations led to identification of novel, selective, and potent small molecule antagonist (22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound 22 was efficacious in a murine allergic inflammation model (ED50 approximately 10 mg/kg).

Application of a probabilistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: effects of moxifloxacin.

Introduction: Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization safety studies, but it has not been characterized in the cynomolgus monkey. This important experimental animal species exhibits pronounced heart rate variability, complicating the temporal evaluation of QT interval data.

Methods: Digitized epicardial ECGs and aortic blood pressures were collected for 20 h in telemetered cynomolgus monkeys (n=6) following the administration of either vehicle or moxifloxacin (10 or 50 mg/kg, p.