For example, placement of the pyridine http://www.selleckchem.com/products/INCB18424.html ring at a different location on the pyridazine ring, Inhibitors,Modulators,Libraries such as in compound MW01 6 189WH, does not generate MAPK inhibitory activity. There fore, compounds with identical compositions to 069A, but different structures, are not able to replicate the kinase inhibitory activity of 069A. Another feature of the model in Fig. 2 relates to the gate keeper residue characteristic of many protein kinases. In p38 and p38 , the gatekeeper residue is Thr106, whereas a larger Met residue is found in the analogous position in found in compound 069A, to generate a p38 MAPK selective inhibitor. Approved drugs and experimental therapeutics that are protein kinase inhibitors generally exhibit inhibition con stants 1M and perturb intracellular signal cascades.
This apparent affinity of efficacious kinase inhibitors is consistent with their ability to compete with the endog enous substrates, for which kinases generally have Km values in the 1 20M range. This requires Inhibitors,Modulators,Libraries that an inhibitor have com parable or better affinity for the kinase than its physiolog ical substrates for efficacy. The affinity Inhibitors,Modulators,Libraries and selectivity of 069A for inhibition of p38 MAPK activity justified further biological characterization of this compound. However, in order to interpret the in vivo biological effects of such an inhibitor, there must be some indication that the com pound is bioavailable, stable and non toxic. Molecular properties and bioavailability of the p38 Inhibition selective Inhibitors,Modulators,Libraries interactions activity and validation of p38 and p38 .
The smaller Thr residue allows bulkier groups, such as the phenyl at position 6 of the pyridazine ring in 069A, to access the hydrophobic pocket found in the kinase active site. Based on structure param eters, therefore, we would Inhibitors,Modulators,Libraries predict that 069A should be a selective inhibitor of p38 and p38 , but not be an inhib itor of the p38 and p38 isoforms. This selectivity was validated as part of an in vitro protein kinase screen done by Millipore, at 20M, 069A showed com plete inhibition of p38 enzyme activity, partial inhibi tion of p38 , and no inhibition of p38 or p38 . In addition, there was little or no inhibition by 069A of 44 other purified protein kinases. Clearly, the pyri dine pharmacophore must be introduced adjacent to the phenyl group in the molecular context of the scaffold, as MAPK inhibitor Molecular properties are physical features of small mole cules that generally define what makes a chemical drug like and likely to be taken up into the bloodstream because they are associated with the ability to exist in aqueous biological free copy milieu yet able to reversibly penetrate biological membranes.