Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase.

Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development.

The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.

A five-minute, but not a fifteen-minute, conditioning trial duration induces conditioned place preference for cocaine administration into the olfactory tubercle.

The establishment of conditioned place preference (CPP) with intracranial injections requires specific injection sites, drug doses, and conditioning trial durations. We examined the role of conditioning trial duration in CPP with cocaine injections into the medial olfactory tubercle. Only those rats that had spent 5 min in the compartments showed CPP for cocaine, while rats that had been removed immediately or spent 15 min following cocaine injections did not show CPP. Effective conditioning trial durations for CPP induced by intracranial cocaine injections are apparently much shorter than those typically used for intracranial injections of other drugs of abuse.

Qualitative perfusion imaging of the human optic nerve.

PURPOSE: Standard methods for the evaluation of human optic nerve perfusion provide limited information. In this pilot study, the authors investigated the feasibility of qualitative perfusion imaging, a recently developed neuroradiologic technique, as a method of assessing human intraorbital optic nerve blood flow. METHODS: Qualitative perfusion imaging (based on magnetic resonance fast spin-echo sequences) was used to study the optic nerves of 7 healthy volunteers and 5 patients with known optic nerve disease. Data regarding both study subject background and alteration in optic nerve signal intensity were statistically analyzed. RESULTS: Control group subjects were significantly younger than study group subjects. No significant differences in optic nerve signal patterns were found within the control group. Comparison of patients with optic neuropathy against the normal composite revealed substantial differences in enhancement characteristics. CONCLUSIONS: Qualitative perfusion imaging of the human optic nerve is feasible and may serve as the basis for more advanced neuroradiologic studies of optic nerve blood flow abnormalities.

Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1.

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.