Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Bioorg Med Chem Lett ; 20(5): 1516-9, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20149651

ABSTRACT

The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.


Subject(s)
Antineoplastic Agents/chemistry , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Drug Discovery , Fingolimod Hydrochloride , High-Throughput Screening Assays , Humans , Mice , Microsomes, Liver/metabolism , Propylene Glycols/chemistry , Propylene Glycols/pharmacology , Rats , Receptors, Lysosphingolipid/metabolism , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity Relationship
2.
J Med Chem ; 51(7): 2227-43, 2008 Apr 10.
Article in English | MEDLINE | ID: mdl-18318469

ABSTRACT

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.


Subject(s)
Hypersensitivity/drug therapy , Indoles/classification , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Spiro Compounds/classification , Spiro Compounds/pharmacology , Animals , Binding Sites , Caco-2 Cells , Cell Membrane Permeability/drug effects , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Dogs , Drug Design , Humans , Indoles/chemistry , Inflammation/drug therapy , Male , Microsomes/drug effects , Microsomes/metabolism , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Spiro Compounds/chemistry , Stereoisomerism , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...