Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor.

Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 08/2004; 14(13):3419-24. DOI: 10.1016/j.bmcl.2004.04.078
Source: PubMed

ABSTRACT Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Condensation of 3-chloropentane-2,4-dione with thioamides gives 1-(thiazol-5-yl)ethanones and subsequent Wittig olefination, followed by nitrile oxide 1,3-dipolar cycloaddition to the resulting prop-1-en-2-yl moiety, delivers racemic 5-(thiazol-5-yl)-4,5-dihydroisoxazoles. When this thiazole and isoxazoline diheterocyclic scaffold has a carboethoxy substituent at C2 of the thiazole ring, aminolysis provides for effective diversification. A 50-member library of various 5-(thiazol-5-yl)-4,5-dihydroisoxazoles is reported.
    Journal of Combinatorial Chemistry 07/2008; 10(4):521-5. · 4.93 Impact Factor
  • Annual Reports in Medicinal Chemistry - ANNU REP MED CHEM. 01/2007; 42:301-320.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Currently, there has been considerable interest in the discovery of original molecules with broad-spectrum anti-HIV activity and favourable pharmacokinetic profiles, to be used as an alternative to the approved anti-HIV/AIDS drugs, should they fail as therapeutics. Five-membered azole heterocycles represent an important class of lead structures for novel anti-HIV drug development. They can serve as versatile building blocks to introduce different new functional groups, (i) as scaffolds to anchor these groups into the optimal space for interactions with the target, (ii) as basic pharmacophore elements to make hydrogen bonds or hydrophobic interaction for facilitating the spatial filling at the binding site, (iii) as ester surrogates to improve metabolic stability, or (iv) as pharmacophoric motif of metal coordination to coordinate metal ions (i.e. magnesium) within the active site of target (i.e. integrase). This article will summarize recent progress in the development of some azoles derivatives that inhibit the replication of HIV-1 and will illustrate the possible functional role(s) of the azole motif in the search for new anti-HIV drugs.
    Current Medicinal Chemistry 01/2011; 18(1):29-46. · 3.72 Impact Factor