1.
J Med Chem
; 53(15): 5801-12, 2010 Aug 12.
Article
in English
| MEDLINE
| ID: mdl-20614889
ABSTRACT
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Subject(s)
Indenes/chemical synthesis , Pyridines/chemical synthesis , Receptors, AMPA/physiology , Sulfonamides/chemical synthesis , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Callithrix , Cell Line , Crystallography, X-Ray , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology
2.
Bioorg Med Chem Lett
; 17(6): 1722-5, 2007 Mar 15.
Article
in English
| MEDLINE
| ID: mdl-17267215
ABSTRACT
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
