Isosteric analogs of lenalidomide and pomalidomide: synthesis and biological activity

Bioorg Med Chem Lett. 2013 Jan 1;23(1):360-5. doi: 10.1016/j.bmcl.2012.10.071.

Alexander L Ruchelman ¹, Hon-Wah Man, Weihong Zhang, Roger Chen, Lori Capone, Jian Kang, Anastasia Parton, Laura Corral, Peter H Schafer, Darius Babusis, Mehran F Moghaddam, Yang Tang, Michael A Shirley, George W Muller

Affiliations

Affiliation

1 Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, United States. aruchelman@celgene.com

PMID: 23168019 DOI: 10.1016/j.bmcl.2012.10.071

Abstract

A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against Cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.

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