Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors. Part 1: Design, synthesis, and biological evaluation

We have identified a novel structural class of protein serine/threonine kinase inhibitors comprised of an aminoimidazo[1,2-a]pyridine nucleus. Compounds from this family are shown to potently inhibit cyclin-dependent kinases by competing with ATP for binding to a catalytic subunit of the protein. Structure-based design approach was used to direct this chemical scaffold toward generating potent and selective CDK2 inhibitors. The discovery of this new class of ATP-site directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis of new medicinal chemistry tool in search for an effective treatment of cancer and other diseases that involve protein kinase signaling pathways.     

Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors

Background

Animal and clinical studies have revealed that focal peripheral nerve axon demyelination is accompanied by nociceptive pain behavior. C-C and C-X-C chemokines and their receptors have been strongly implicated in demyelinating polyneuropathies and persistent pain syndromes. Herein, we studied the degree to which chronic nociceptive pain behavior is correlated with the neuronal expression of chemokines and their receptors following unilateral lysophosphatidylcholine (LPC)-induced focal demyelination of the sciatic nerve in rats.

Results

Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. This behavior was accompanied by a bilateral increase in the numbers of primary sensory neurons expressing the chemokine receptors CCR2, CCR5, and CXCR4 by POD14, with no change in the pattern of CXCR3 expression. Significant increases in the numbers of neurons expressing the chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2), Regulated on Activation, Normal T Expressed and Secreted (RANTES/CCL5) and interferon γ-inducing protein-10 (IP-10/CXCL10) were also evident following nerve injury, although neuronal expression pattern of stromal cell derived factor-1α (SDF1/CXCL12) did not change. Functional studies demonstrated that acutely dissociated sensory neurons derived from LPC-injured animals responded with increased [Ca²⁺]_i following exposure to MCP-1, IP-10, SDF1 and RANTES on POD 14 and 28, but these responses were largely absent by POD35. On days 14 and 28, rats received either saline or a CCR2 receptor antagonist isomer (CCR2 RA-[R]) or its inactive enantiomer (CCR2 RA-[S]) by intraperitoneal (i.p.) injection. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia.

Conclusion

These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain.     

Relationships between Solutes,Nutrients, and the Biofilm in Sediments of Floodplain Karstic and Alluvial Springs

Two pairs of springs were surveyed in the floodplain of the Upper Rhône River. Each pair included a karstic (upstream) and an alluvial (downstream) spring in the same catchment. Various physical, chemical, and biological factors were measured in the water and the sediment. The study showed karstic and alluvial spring typology. In each pair, the karstic springs were characterized by higher alkalinity, whereas alluvial springs were fed both by karstic groundwater and Rhône River water with higher sulphate content. Organic matter dynamics and retention processes were different in each spring. The distribution and abundance of fine sediment played a prominent role in the storage of particulate organic carbon and the development of microbial biomass and activity. The hydrological cycle governed organic and inorganic nutrient fluxes, and was, with temperature, the main factor influencing microbial and macroinvertebrate dynamics. The high amount of organic matter in one alluvial spring was correlated with high microbial biomass and activity.     

New aza(nor)adamantanes are agonists at the newly identified serotonin 5-HT4 receptor and antagonists at the 5-HT3 receptor

New aza(nor)adamantanes , , and are described which exhibit properties of both 5-HT4 agonism and 5-HT3 antagonism. In particular, compound [SC-52491], an azanoradamantane, exhibits an EC₅₀ of 51 nM in a functional model of 5-HT₄ agonism and potent antagonism, Ki = 1.2 nM, at the 5-HT₃ receptor.     

Storage and dynamics of organic matter in different springs of small floodplain streams

The flow of groundwater through the sediment layer (underflow or hyporheic zone) of streams and at the origin of streams can influence organic matter uptake dynamics of floodplain. The River Rhône floodplain has limestone foothills. Here we studied 2 karstic and 2 interstitial springs differing by aquifer geology. Organic matter, physico-chemical conditions were compared between these springs during two seasons (from March to September 1989) and at different depths (0, –20 cm, –40 cm).Temperatures indicated large differences in underflow between springs, in their relation to the surrounding environment, and between seasons. Springs are well oxygenated, with differences between layers. Cultivated fields supply interstitial springs with nitrates, and pools are nutrient traps. DOC was heterogeneous in space and time and correlates with VFPOC. Particulate nutrients were correlated with available surface area of sediment grains. Physical conditions of each spring were prominent in determining storage and turnover of organic matter. Each spring, by its own characteristics and dynamics regulating stability and turnover, had an effect or control on storage, transport and retention of organic matter (quality, quantity). These springs offer an example of the heterogeneity, and give a view of the diversity of patches within a floodplain. The data suggest that groundwater flow of springs may be a major factor in the functioning of floodplain tributaries.     

Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases

Structure-based design approach was successfully used to guide the evolution of imidazopyridine scaffold yielding new structural class of highly selective inhibitors of cyclin dependent kinases that were able to form a new interaction with an identified residue of the protein, Lys89. Compounds from this series have shown no detectable effect when tested against a representative set of other serine/threonine kinases such as GSK3beta, CAMKII, PKA, PKC-alpha,beta,epsilon,gamma. Compound 2i inhibits proliferation in HCT 116 cells in tissue culture. Synthesis, co-crystal structure of CDK2 in complex with compound 2i, and preliminary SAR study are disclosed.