Discovery and lead optimization of a novel series of CC chemokine receptor 1 (CCR1)-selective piperidine antagonists via parallel synthesis.
J Med Chem
; 55(22): 9643-53, 2012 Nov 26.
Article
em En
| MEDLINE
| ID: mdl-23075267
ABSTRACT
A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Microssomos Hepáticos
/
Monócitos
/
Quimiotaxia
/
Receptores CCR
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article