Biomedical subjects

George V De Lucca

Publications and source records attributed to George V De Lucca.

3 recordsLinked to original sources

PubMed2006

Recent developments in CCR3 antagonists.

Selective eosinophil recruitment into inflammatory sites and their subsequent activation is a characteristic of allergic diseases, such as asthma, rhinitis and atopic dermatitis. CC chemokine receptor-3 (CCR3) is the principal mediator of eosinophil chemotaxis and is expressed on a variety of inflammatory cells associated with allergic responses; these cells include basophils, mast cells and T-helper-2 lymphocytes, and resident tissue cells such as airway epithelium. Animal studies suggest that CCR3 is a prominent mediator of allergic responses and that antagonizing the receptor will lead to a reduction in airway inflammation. The potential importance of CCR3 in allergic inflammation has made this receptor a target for drug development. This review summarizes the efforts in this research area that have been reported in the last two years.

Animals↗

PubMed2005

Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.

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.

Animals↗

PubMed2002

Discovery and structure-activity relationship of N-(ureidoalkyl)-benzyl-piperidines as potent small molecule CC chemokine receptor-3 (CCR3) antagonists.

Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.

Animals↗