1. Academic Validation
  2. Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication

Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication

  • J Med Chem. 2010 Apr 22;53(8):3376-88. doi: 10.1021/jm100073m.
Renato T Skerlj 1 Gary J Bridger Al Kaller Ernest J McEachern Jason B Crawford Yuanxi Zhou Bem Atsma Jonathon Langille Susan Nan Duane Veale Trevor Wilson Curtis Harwig Sigrid Hatse Katrien Princen Erik De Clercq Dominique Schols
Affiliations

Affiliation

  • 1 Genzyme Corp., 153 Second Avenue, Waltham, Massachusetts 02451, USA. renato.skerlj@genzyme.com
Abstract

The redesign of azamacrocyclic CXCR4 Chemokine Receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 microM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 Antagonist that was developed for the treatment of HIV-1 Infection.

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