Analysis of the Mechanism by Which the Small-Molecule CCR5 Antagonists SCH-351125 and SCH-350581 Inhibit Human Immunodeficiency Virus Type 1 Entry

Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5

In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects

Substantial evidence implicates -amyloid (A) peptides in the etiology of Alzheimer’s disease (AD). A is produced by the proteolytic cleavage of the amyloid precursor protein by - and -secretase suggesting that -secretase inhibition may provide therapeutic benefit for AD. Although many -secretase inhibitors have been shown to be potent at lowering A, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another -secretase substrate. Here we describe the in vivo characterization of the novel -secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A. However, additional studies revealed that both partial but sustained lowering of Aand complete but less sustained lowering of A were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A lowering by -secretase inhibitors, it is possible to obtain robust and sustained lowering of A without evidence of Notch-related side effects

Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer’s disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate <b>18a­(−)</b> features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs

Synthesis and SAR Studies of Fused Oxadiazines as γ‑Secretase Modulators for Treatment of Alzheimer's Disease

Fused oxadiazines (<b>3</b>) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure–activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds <b>8r</b> and <b>8s</b> that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound <b>8s</b> confirm that the oxadiazine series of compounds are potent GSMs