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

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

  • J Med Chem. 2005 Mar 24;48(6):2194-211. doi: 10.1021/jm049530m.
George V De Lucca 1,  Ui Tae Kim,  Brian J Vargo,  John V Duncia,  Joseph B Santella 3rd,  Daniel S Gardner,  Changsheng Zheng,  Ann Liauw,  Zhang Wang,  George Emmett,  Dean A Wacker,  Patricia K Welch,  Maryanne Covington,  Nicole C Stowell,  Eric A Wadman,  Anuk M Das,  Paul Davies,  Swamy Yeleswaram,  Danielle M Graden,  Kimberly A Solomon,  Robert C Newton,  George L Trainor,  Carl P Decicco,  Soo S Ko
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Company, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. george.delucca@bms.com
PMID: 15771462 DOI: 10.1021/jm049530m
Abstract

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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z