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Updated: Aug 6, 2026

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Novel, orally bioavailable gamma-aminoamide CC chemokine receptor 2 (CCR2) antagonists
Alexander Pasternak1, Dominick Marino, Pasquale P Vicario
1Department of Medicinal Chemistry and Department of Immunology/Rheumatology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. alexander_pasternak@merck.com
Abstract:
Through modification of a screening hit we have discovered a structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), which has subsequently served as the departure point for an ongoing program targeting CCR2 antagonists. Optimization of 11 leading to antagonists 26 and 37 is described. Antagonist 26 was shown to have good oral bioavailability in rats. Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM).
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