[Show abstract][Hide abstract] ABSTRACT: Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Methods for the preparation of (3S)-3-(4-fluorobenzyl)piperidine (2) and its mandelate salt (9) are described. The first generation synthesis started from 3-benzylpiperidone, and required Boc protection of the nitrogen for efficient separation of the enantiomers using chromatography on a chiral stationary phase. Subsequently, a resolution method using (R)-mandelic acid, produced high %ee salt 9 after recrystallization and eliminated the need for Boc protection. The third generation route, starting from pyridine-3-carboxaldehyde, led to a streamlined synthesis of racemate 2 and was optimized for producing multi-hundred gram quantities of the chiral salt.
[Show abstract][Hide abstract] ABSTRACT: Syntheses of three n-butyl side chain hydroxylated metabolites of Roxifiban (5, 6a and 6b) are reported. Initial use of benzyl as hydroxyl protecting group gave poor yield during its removal by catalytic hydrogenation, due to complication from N-O cleavage of the isoxazoline. This problem was eliminated by the use of TBDMS as the hydroxyl protecting group. The chemical structures of these metabolites as well as the intermediates have been fully characterized.