Social behaviour and heart rate in tammar wallabies (Macropodidae: Macropus eugenii)

In an enclosed group of tammar wallabies the behaviour of all individuals and the heart rate (HR) of three males were recorded simultaneously. The social structure was characterized by the dominance relationships between the males and the sexual preference of all males for the oldest female. During non-oestrus, dominance was obvious when a male intervened terminating the sexual behaviour of a subdominant one. The relatively low amount of agonistic behaviour between the males is assumed to be due to the clear dominance relationships. Locomotion as well as sexual and agonistic behaviour were accompanied by an acceleration of HR. The HR pattern depended on the intensity of the behaviour, its duration and the animal's identity. Commonly performed sexual behaviour and approach/retreat encounters gave rise to HR values not different from HR values during locomotor activity without interactive components. Social events that occurred infrequently—like fights, and the mating of an oestrous female—were accompanied by strong accelerations of HR indicating high cardiac effort. The mild cardiac activity during common social encounters is consistent with a strategy of maximizing energy conservation. HR patterns during specific behaviour could not entirely be accounted for by the energetic costs of activity. Spreading the forelimbs in response to specific stimuli—like the fly-over of raptors—was indicative of a strong HR response even if the animal was motionless. During specific social encounters like the sexual behaviour of the alpha-male following an intervention—HR responses revealed that arousal might exceed motor activity in affecting HR. Individual differences of these HR responses are attributed to the age, experience and social status of a male.     

Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30 mpk BID for 2.5 days.     

Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists

A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.     

Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.     

Gold nanoparticles decorated with oligo(ethylene glycol) thiols: kinetics of colloid aggregation driven by depletion forces

We have studied the kinetics of the phase-separation process of mixtures of colloid and protein in solutions by real-time UV-vis spectroscopy. Complementary small-angle X-ray scattering (SAXS) was employed to determine the structures involved. The colloids used are gold nanoparticles functionalized with protein resistant oligo(ethylene glycol) (OEG) thiol, HS(CH(2))(11)(OCH(2)CH(2))(6)OMe (EG6OMe). After mixing with protein solution above a critical concentration, c*, SAXS measurements show that a scattering maximum appears after a short induction time at q = 0.0322 A(-1), which increases its intensity with time but the peak position does not change with time, protein concentration and salt addition. The peak corresponds to the distance of the nearest neighbor in the aggregates. The upturn of scattering intensities in the low q-range developed with time indicating the formation of aggregates. No Bragg peaks corresponding to the formation of colloidal crystallites could be observed before the clusters dropped out from the solution. The growth kinetics of aggregates is followed in detail by real-time UV-vis spectroscopy, using the flocculation parameter defined as the integral of the absorption in the range of 600-800 nm wavelengths. At low salt addition (<0.5 M), a kinetic crossover from reaction-limited cluster aggregation (RLCA) to diffusion-limited cluster aggregation (DLCA) growth model is observed, and interpreted as being due to the effective repulsive interaction barrier between colloids within the depletion potential. Above 0.5 M NaCl, the surface charge of proteins is screened significantly, and the repulsive potential barrier disappeared, thus the growth kinetics can be described by a DLCA model only.     

Design,synthesis, and structure–activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline γ-secretase inhibitors

In this Letter, we report our strategy to design potent and metabolically stable γ-secretase inhibitors that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose.     

A series of C-terminal amino alcohol dipeptide A beta inhibitors

Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.