298181-76-7Relevant articles and documents
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
Skerlj, Renato T.,Bridger, Gary J.,Kaller, Al,McEachern, Ernest J.,Crawford, Jason B.,Zhou, Yuanxi,Atsma, Bem,Langille, Jonathon,Nan, Susan,Veale, Duane,Wilson, Trevor,Harwig, Curtis,Hatse, Sigrid,Princen, Katrien,De Clercq, Erik,Schols, Dominique
body text, p. 3376 - 3388 (2010/09/05)
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 IC50 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 IC50 of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 μM. 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.
Chemokine receptor binding heterocyclic compounds
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Page column 16, (2008/06/13)
This invention relates to a novel class of heterocyclic compounds that bind chemokine receptors, inhibiting the binding of their natural ligands thereby. These compounds result in protective effects against infection by HIV through binding to chemokine receptors, including CXCR4 and CCR5, thus inhibiting the subsequent binding by these chemokines. The present invention provides a compound of Formula I wherein, W is a nitrogen atom and Y is absent or, W is a carbon atom and Y═H; R1to R7may be the same or different and are independently selected from hydrogen or straight, branched or cyclic C1-6alkyl; R8is a substituted heterocyclic group or a substituted aromatic group Ar is an aromatic or heteroaromatic ring each optionally substituted at single or multiple, non-linking positions with electron-donating or withdrawing groups; n and n′ are independently, 0-2; X is a group of the formula: Wherein, Ring A is an optionally substituted, saturated or unsaturated 5 or 6-membered ring, and P is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur or oxygen atom. Ring B is an optionally substituted 5 to 7-membered ring. Ring A and Ring B in the above formula can be connected to the group W from any position via the group V, wherein V is a chemical bond, a (CH2)n″group (where n″=0-2) or a C═O group. Z is, (1) a hydrogen atom, (2) an optionally substituted C1-6alkyl group, (3) a C0-6alkyl group substituted with an optionally substituted aromatic or heterocyclic group, (4) an optionally substituted C0-6alkylamino or C3-7cycloalkylamino group, (5) an optionally substituted carbonyl group or sulfonyl. These compounds further include any pharmaceutically acceptable acid addition salts and metal complexes thereof and any stereoisomeric forms and mixtures of stereoisomeric forms thereof.
