piperidines and Acquired-Immunodeficiency-Syndrome

LF 1695, a synthetic immunomodulator with a low mol. wt, has been shown to exert its activity on T-lymphocytes and macrophages. It induced T-cell differentiation of bone marrow precursor cells which acquired the expression of CD3, CD4 and/or CD8. It increased lymphocyte proliferative responses to mitogens, antigens and allogeneic cells. IL-2 production was increased in Con A-activated but not in resting lymphocytes. Added to macrophages, LF 1695 augmented IL-1 production and LTB4 synthesis but it decreased PGE2 secretion. Hematological reconstitution of animals, following bone marrow alteration by irradiation or chemotherapy, was accelerated. Many of the effects of this compound may result from the enhancement of interleukin production, by macrophages especially. After investigations of LF 1695 effect on HIV-infected cells, clinical trials have been initiated in AIDS and ARC patients.

Topics: Acquired Immunodeficiency Syndrome; Adjuvants, Immunologic; Humans; Macrophages; Piperidines; T-Lymphocytes

The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Butanes; CCR5 Receptor Antagonists; Combinatorial Chemistry Techniques; Ether-A-Go-Go Potassium Channels; HIV; HIV Infections; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship; Tropanes

We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Chemokine CCL5; Cyclic N-Oxides; HIV-1; Humans; Macaca fascicularis; Male; Mice; Mice, SCID; Oximes; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley