Author: Lori L. Bostrom ; Maryanne Covington ; Danielle Graden ; Patricia K. Welch ; Robert C. Newton ; Douglas G. Batt ; Ilona Kariv ; Swamy Yeleswaram ; Jeffrey G. Varnes ; Soo S. Ko ; Percy H. Carter ; David D. Christ ; Shon K. Booker ; Carl P. Decicco ; Yevgeniya Orlovsky ; Erin McLaughlin ; James R. Pruitt ; Anuk M. Das ; Krishna G. Vaddi ; Gregory C. Houghton ; Kimberly A. Solomon ; Nicole C. Stowell ; Paul Davies ; Eric A. Wadman ; Dean A. Wacker

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

01 Mar 2005·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of CC Chemokine Receptor-3 (CCR3) Antagonists with Picomolar Potency

Q1 · MEDICINE

Article

Author: Trainor, George L. ; Liauw, Ann ; Gardner, Daniel S. ; Davies, Paul ; Yeleswaram, Swamy ; Welch, Patricia K. ; Stowell, Nicole C. ; Duncia, John V. ; Kim, Ui Tae ; Decicco, Carl P. ; Wang, Zhang ; Das, Anuk M. ; Wadman, Eric A. ; Vargo, Brian J. ; Santella, Joseph B. ; Wacker, Dean A. ; Newton, Robert C. ; Emmett, George ; Covington, Maryanne ; Graden, Danielle M. ; Ko, Soo. S. ; De Lucca, George V. ; Solomon, Kimberly A. ; Zheng, Changsheng

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	US	Bristol Myers Squibb Co.	-
Rhinitis, Allergic	Phase 1	US	Bristol Myers Squibb Co.	-

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