A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
Security issues are one of the major deterrents to Web Services adoption in mission critical applications and to the realization of the dynamic e-Business vision of Service Oriented Computing. Role Based Access Control (RBAC) is a common approach for authorization as it greatly simplifies complex authorization procedures in enterprise information systems. However, as most RBAC implementations rely on the manual setup of pre-defined user-ID and password combinations to identify the particular user, this makes it very hard to conduct dynamic e-Business as the service requestor and service provider must have prior knowledge of each other before the transaction. This paper proposes a new Web Services security architecture which unifies the authorization and authentication processes by extending current digital certificate technologies. It enables secure Web Service authorization decisions between parties even if previously unknown to each other and it also enhances the trustworthiness of service discovery.
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