On the Average Time- and Frequency-Pattern of Photic Flicker Response in Relation to Intrinsic Alpha Activity Verified by a New Simple Method

Delivering photic flicker stimulations from about 8 to 12 flashes per second for about 60 seconds continuously to relaxed normal adult human subject, the average properties of the driven EEG waves are obtained by applying a new practical crosscorrelation method to eliminate the irrelevant oscillations to the stimulation. The average time-pattern of the intrinsic alpha activity was carved in relief by a new simple autocorrelation method, which is originally demonstrated here. The EEGs are traced from the occipital, parietal, temporal and frontal regions by monopolar technique. Even immediately after the initiation of flicker stimulation, the response wave of the stimulating frequency was driven and tended to build up gradually to the maximum average intensity in the course of contiunal stimulation, especially in the occipital region, showing some fluctuation in size. The average distribution of the driven wave over the scalp was similar to those of the relaxed intrinsic alpha wave activity, in size and phase angle. From these evidences it would be assumed at least for the first approximation that the driven waves are produced from a generator essentially similar to what acts in relaxed state. In the occipital region, the EEG response was easily driven more intensely the intrinsic alpha activity in the relaxed state by a photic flicker stimulation with a higher frequency than that of relaxed alpha activity, whereas weaker response tended to be driven by lower frequency of stimulation. In other regions, however, a reverse tendency was observed immediately after the initiation of the stimulation

Small molecules for bone diseases

Drug discovery for bone diseases has made progress in the last years, and also the research area has dynamically shifted from historical targets (Bisphosphonate, PTH and Calcitonin) to newly confirmed targets or targets re-visited which were biologically validated in the past. Cathepsin K inhibitor would be very closed to lanch into the market, however there are lots of progress and new findings in other relevant targets, which we discuss in this paper

Orally Bioavailable Cathepsin K inhibitors with Pyrrolopyrimidine Scaffold

The recent emergence of osteoporosis as a major health threat in people of advanced age has intensified the search for novel and effective pharmacologic treatments. Given that bone resorption is exceeding bone formation, a reduction in bone mass leads to disease conditions including; post-menopausal osteoporosis and tumor-induced osteolysis. Our efforts in this area have focused on the optimization of non-peptidic cathepsin K inhibitors for affinity and selectivity, from an heteroaromatic nitrile as a novel scaffold. This approach has resulted in the discovery of the potent and selective cathepsin K inhibitor, 44. The concentration of cathepsin K inhibitors, including compound 44, in the target tissues such as bone marrow cavity were predictive parameters for antibone resorptive efficacy in vivo in the rat. The high level of distribution to the bone marrow was also observed for compounds containing pyrrolopyrimidines with novel spiro-structures as the P3 moiety. In a monkey study with the representative inhibitor 44, the antibone resorptive efficacy was detected 8 h after the compound administration. The efficacy persisted throughout the repeated treatment period of 14 days without any evidence for the development of tolerance. This article constitutes a near comprehensive review of the published scientific literature on small molecule non-peptidic inhibitors for cathepsin K developed by Novartis

The Central Valine Concept Provides an Entry in a New Class of Non Peptide Inhibitors of the P53-MDM2 Interaction

Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction , we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction

Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency achieved in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line

New Pyrazolo[1,5a]pyrimidines as Orally Active Inhibitors of Lck

A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies towards activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency