Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series

doi:10.1016/j.bmcl.2008.02.015

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 6, 15 March 2008, Pages 1869-1873

https://doi.org/10.1016/j.bmcl.2008.02.015 Get rights and content

Abstract

SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC₅₀ 3.2 nM; MCP-1-Induced Chemotaxis IC₅₀ 0.83 nM; Ca²⁺ Flux IC₅₀ 7.5 nM].

Graphical abstract

SAR studies of a 3-amino pyrrolidine series led to the identification of potent CCR2b antagonists with low nanomolar activity in binding and functional assays as exemplified by compound 71.

Section snippets

Acknowledgments

The authors wish to acknowledge Dr. Erin Bradley and Dr. David Spellmeyer for computational support on this program, Dr. Dan Kassel, Dr. Lu Zeng and Ms. Xiaoli Wang for their technical expertise in setting up systems for mass triggered HPLC purification, Ms. Akiko Takeuchi for her expertise on the Ca²⁺ flux inhibition assay and Dr. Takeshi Hara and Dr. Seizi Kurozumi for general support.

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^†: Present address: Pfizer Global Research & Development, La Jolla Laboratories, Discovery Chemistry, 10614 Science Center Drive (CB6), San Diego, CA 92121, USA.

^‡: Present address: Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.

^§: Present address: Bizen Chemical Co., Ltd, Research and Development Department, 363-Tokutomi, Kumayama-Cho, Akaiwa-Gun, Okayama 709-0716, Japan.

^¶: Present address: Vertex, 11010 Torreyana Road, San Diego, CA 92121, USA.

^††: Present address: LEAD Therapeutics, Inc., 999 Bayhill Drive, Suite 130, San Bruno, CA 94066, USA.

^‡‡: Present address: Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA.

View full text

Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series

Abstract

Graphical abstract

Section snippets

Acknowledgments

Blood

Drug Discov. Today

Pharmacol. Rev.

Cytokine Growth Factor Rev.

Curr. Opin. Chem. Biol.

Nat. Rev. Drug Disc.

N. Eng. J. Med.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

J. Exp. Med.

J. Pathol.

J. Exp. Med.

J. Med. Chem.

J. Med. Chem.

J. Clin. Invest.

Nature

Atherosclerosis

J. Exp. Med.