1.
Bioorg Med Chem Lett
; 22(24): 7702-6, 2012 Dec 15.
Article
in English
| MEDLINE
| ID: mdl-23142617
ABSTRACT
The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.
Subject(s)
Drug Discovery , Hydroxamic Acids/pharmacology , Piperidines/pharmacology , Receptors, CCR3/antagonists & inhibitors , Receptors, Histamine H1/metabolism , Animals , Hepatocytes/chemistry , Hepatocytes/metabolism , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/metabolism , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Piperidines/chemistry , Piperidines/metabolism , Rats , Structure-Activity Relationship , Tissue Distribution
2.
Bioorg Med Chem Lett
; 22(24): 7707-10, 2012 Dec 15.
Article
in English
| MEDLINE
| ID: mdl-23116889
ABSTRACT
The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.
