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The cannabinoid receptors CB(1) and CB(2) are class A G-protein-coupled receptors. It is well known that cannabinoid receptor agonists produce relief of pain in a variety of animal models by interacting with cannabinoid receptors. CB(1) receptors are located centrally and peripherally, whereas CB(2) receptors are expressed primarily on immune cells and tissues. A large body of preclinical data supports the hypothesis that either CB(2)-selective agonists or CB(1) agonists acting at peripheral sites, or with limited CNS exposure, will inhibit pain and neuroinflammation without side effects within the CNS. There has been a growing interest in developing cannabinoid agonists. Many new cannabinoid ligands have been synthesized and studied covering a wide variety of novel structural scaffolds. This review focuses on the present development of cannabinoid agonists with an emphasis on selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists for treatment of inflammatory and neuropathic pain.
Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 μM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aβ levels in cerebrospinal fluid (CSF).
Evidence has been presented (Kukar et al. 2008 Nature 453, 925-929) that certain γ-secretase modulators (GSMs) target the 99 residue C-terminal domain (C99) of the amyloid precursor protein, a substrate of γ-secretase, but not the protease complex itself. Here, NMR results demonstrate a lack of specific binding of these GSMs to monodisperse C99 in LMPG micelles. In addition, results indicate that C99 was likely to have been aggregated in some of the key experiments of the previous work, and that binding of GSMs to these C99 aggregates is also of a non-specific nature.Among the therapeutic targets for Alzheimer's disease (AD), the amyloid pathway has long been paramount (1). Familial early-onset AD (FAD) is associated with autosomal dominant mutations in the amyloid precursor protein (APP) and in the catalytic subunits (presenilin 1 and presenilin 2) of the intramembrane protease that processes it, γ-secretase (2). According to the amyloid hypothesis, oligomeric forms of Aβ are the principal agents underlying disease pathogenesis (1). The Aβ peptide is generated by proteolysis of APP. Cleavage of APP by β-secretase yields C99 2 , which is then heterogeneously processed by γ-secretase to generate Aβ species with a variety of lengths, principally Aβ40 (3). Familial AD is associated with an increase in the Aβ42/Aβ40 ratio, with Aβ42 being the primary species deposited in the brain parenchyma of most individuals with AD (4). Because Aβ is thought to be central to the pathogenesis of AD, inhibiting its production is a potential therapeutic strategy (1). Although significant progress has been made in the identification and development of potent γ-secretase inhibitors, their clinical application has been limited by significant toxicities resulting from interference with processing of other γ-secretase substrates, particularly Notch (5). Indeed, γ-secretase is a highly promiscuous protease with more than sixty identified targets (6).The discovery that a subset of non-steroidal anti-inflammatory drugs could selectively reduce Aβ42 production without abrogating Notch cleavage suggested an alternative therapeutic strategy for AD (7). The Aβ42-lowering activity of these γ-secretase modulators (GSMs) was recapitulated in cell-free assays of γ-secretase activity. Several groups have produced data suggesting that GSMs interact allosterically with presenilin, thereby modifying the enzyme's conformation (8-10). Moreover, GSMs were observed to influence the cleavage of an unrelated substrate by signal peptide peptidase -an enzyme with homology to the presenilin subunit of γ-secretase, suggesting that the modulators interact with the enzyme rather than substrate † This work was supported by grants from the US NIH (PO1 GM080513, to CRS) and from the Alzheimer's Association (IIRG-07-59379, to CRS). A recent report from the Golde laboratory, however, postulates that GSMs specifically target APP and its C-terminal derivatives, providing an alternative explanation to the apparent specificity that GSMs exert on cleavage of C99 (1...
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