Adms

Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC 50 = 8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC 50 = 9.7 nM).

2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.

Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.

Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central b-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC 50 = 21 nM) with excellent in vivo activity and pharmacokinetic profile.

Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.

Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.

Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.

A search is reported for the pair production of a new quark, b ′ , with at least one b ′ decaying to a Z boson and a bottom quark. The data, corresponding to 2.0 fb −1 of integrated luminosity, were collected from pp collisions at √ s = 7 TeV with the ATLAS detector at the CERN Large Hadron Collider. Using events with a b-tagged jet and a Z boson reconstructed from opposite-charge electrons, the mass distribution of large transverse momentum b ′ candidates is tested for an enhancement. No evidence for a b ′ signal is detected in the observed mass distribution, resulting in the exclusion at 95% confidence level of b ′ quarks with masses m b ′ < 400 GeV that decay entirely via b ′ → Z + b. In the case of a vector-like singlet b ′ mixing solely with the third Standard Model generation, masses m b ′ < 358 GeV are excluded. (c)

A search for diphoton events with large missing transverse momentum has been performed using proton-proton collision data at √ s = 7 TeV recorded with the ATLAS detector, corresponding to an integrated luminosity of 4.8 fb −1 . No excess of events was observed above the Standard Model prediction and model-dependent 95 % confidence level exclusion limits are set. In the context of a generalised model of gauge-mediated supersymmetry breaking with a bino-like lightest neutralino of mass above 50 GeV, gluinos (squarks) below 1.07 TeV (0.87 TeV) are excluded, while a breaking scale Λ below 196 TeV is excluded for a minimal model of gauge-mediated supersymmetry breaking. For a specific model with one universal extra dimension, compactification scales 1/R < 1.40 TeV are excluded. These limits provide the most stringent tests of these models to date.

AbstractÐBenzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable b 3 adrenergic receptor (AR) agonists. The 4-tri¯uormethoxy substituted 5-benzyl oxadiazole 5f has an EC 50 of 8 nM in the b 3 AR agonist assay with 100-fold selectivity over b 1 and b 2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 AE 4%, with a half-life of 3.8 AE 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED 50Gly =0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg. #