Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication Renato Skerlj a,⇑ , Gary Bridger b , Ernest McEachern b , Curtis Harwig b , Chris Smith b , Alan Kaller b , Duane Veale b , Helen Yee b , Krystyna Skupinska b , Rossana Wauthy b , Letian Wang b , Ian Baird b , Yongbao Zhu b , Kate Burrage b , Wen Yang b , Michael Sartori b , Dana Huskens c , Erik De Clercq c , Dominique Schols c a Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA b AnorMED, Inc., 200-20353 64th Avenue, Langley, British Columbia, Canada V2Y 1N5 c Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium article info Article history: Received 2 December 2010 Revised 4 January 2011 Accepted 6 January 2011 Available online 11 January 2011 Keywords: CXCR4 Chemokine receptor HIV-1 AMD070 Structure–activity relationship abstract A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog. Ó 2011 Elsevier Ltd. All rights reserved. Recent recommendations of the International AIDS Society Panel-USA on antiretroviral therapy (ART) for HIV-infected adults state, that frequent monitoring of patient HIV-1 RNA is necessary to identify and manage treatment failure, with the goal being suppression of HIV-1 RNA below quantification limits. 1 Frequent monitoring is necessary to identify virologic failure due to the emergence of resistance variants. Recently approved drugs with novel mechanisms of action such as raltegravir 2 and mariviroc 3 that target HIV integrase and the chemokine receptor CCR5 add to the armory of drugs available to treat HIV and provide additional treatment options for managing resistance. The discovery of the chemokine receptors CXCR4 and CCR5 in 1996 as co-receptors for HIV for cell entry by HIV-1 4 prompted a concerted research effort to discover novel antagonists of these receptors. Our longstanding research interest in CXCR4 led to the first clinical proof of concept that blocking CXCR4 with a small molecule antagonist, AMD3100, results in viral load reduction in T-tropic (X4) HIV-1 infected patients. 5 This was followed by the discovery and development of the first orally bioavailable CXCR4 antagonist AMD070 6 that also demonstrated viral load reduction in T-tropic (X4) HIV-1 infected patients. 7 In addition to HIV, CXCR4 and its specific ligand, CXCL12 [stromal cell derived factor-1 (SDF-1)], have been implicated to play a role in tumor progression, angiogenesis, metastasis and survival. 8 Moreover, the CXCR4/ CXCL12 axis also plays an important role in the homing and reten- tion of progenitor cells in the bone marrow microenvironment. 9 Consequently, based on compelling clinical data, plerixafor (AMD3100) was approved in the US in 2008 for mobilization of hematopoietic stem cells in patients with non-Hodgkins’s lymphoma (NHL) 10 and multiple myeloma (MM). 11 Recently we reported on our medicinal chemistry efforts that led to the design and synthesis of oral agents such as AMD070 6 as well as novel heterocyclic analogs of AMD070. 12 In addition researchers from GlaxoSmithKline have reported on an extensive analog program of AMD070. 13 In this Letter, we disclose our efforts on modifying AMD070 (1) by sequentially replacing the benzimid- azole ring with a substituted pyridine ring (2), opening up the tetrahydroquinoline ring (3), and combining both of these modifi- cations to afford the open chain analogs (4) while still maintaining potent HIV-1 inhibition (Fig. 1). The primary data used to drive the SAR were the ability of these compounds to inhibit replication of HIV-1 NL4.3, using exclusively CXCR4 for viral entry into its target cells. In addition, the ability of these compounds to specifically interact with CXCR4 were also 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.01.021 ⇑ Corresponding author. Tel.: +1 781 434 3684; fax: +1 781 672 5823. E-mail address: renato.skerlj@genzyme.com (R. Skerlj). Bioorganic & Medicinal Chemistry Letters 21 (2011) 1414–1418 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl