A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.
The syntheses of four classes of novel ruthenium(ii) complexes with chiral bidentate cyclopentadienylphosphine ligands and their application in asymmetric catalysis are described. This approach to an enantioselective reconstitutive condensation was assisted by molecular modeling to deal with the question of asymmetric induction at the metal center and lead to a more precise understanding of the enantiodiscriminating step. The catalysts were routinely tested towards the enantioselective reconstitutive condensation of ethyl undecynoate and cyclohexyl-2-propen-1-ol to provide ethyl 12-cyclohexyl-11-oxo-13-tetradecenoate.
As the potential for ruthenium‐catalyzed reactions other than hydrogenation increases, the importance of asymmetric complexes grows. With the aid of molecular modeling, four classes of novel ruthenium(II) complexes with chiral bidentate cyclopentadienylphosphine ligands were designed and tested for asymmetric induction in a ruthenium‐catalyzed reconstructive addition (see figure).
A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).
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