Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet ␤-cell proliferation and glucosedependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). diabetes ͉ exendin-4 ͉ neurodegeneration ͉ neuroprotection ͉ stroke

Like acetylcholinesterase , butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused longterm inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra-and extracellular ␤-amyloid precursor protein, and secreted ␤-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower ␤-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.anticholinesterase ͉ long-term potentiation ͉ dementia ͉ memory ͉ neurodegeneration

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.

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The reduction in levels of the potentially toxic amyloid-␤ peptide (A␤) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the A␤ precursor protein (␤APP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces ␤APP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in ␤APP processing. Phenserine treatment resulted in decreased secretion of soluble ␤APP and A␤ into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of ␤APP protein expression by phenserine was posttranscriptional as it suppressed ␤APP protein expression without altering ␤APP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5-mRNA leader sequence of ␤APP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces A␤ levels by regulating ␤APP translation via the recently described iron regulatory element in the 5-untranslated region of ␤APP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of ␤APP expression that can result in a substantial reduction in the level of A␤. T he major pathological hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative condition leading to loss of memory, are characterized by the appearance of senile plaques that are primarily composed of A␤ and neurofibrillary tangle aggregates (1, 2). A␤, a 40-to 42-residue peptide, is derived from a larger protein, ␤APP (695-770 residues) whose biological functions remain to be fully determined but whose pathological role may be separated on the basis of its final proteolyzed form (1, 3). ␤APP derivatives are generated by three enzymatic activities termed ␣-, ␤-, and ␥-secretases to produce different protein fragments that are either neuroprotective or amyloidogenic. Recently, four groups have identified an aspartyl protease with ␤-secretase-like properties (4-7) that may serve as a therapeutic marker. However, its value as a target for drug development is complicated by its location within two (plasma and Golgi) membranes. Furthermore, the role of alternative compensatory activities remains unclear. Indeed, a second enzyme, Thimet oligopeptidase, was found capable of ␤-secretase activity in transfected COS cells (8). A major pharmaceutical industry focus has been to look for agents that reduce amyloidogenic processing using compounds that can manipulate ␤APP to produce nonamyloidogenic by-products. However, it is important...

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Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective in improving cognitive, behavioral and functional impairments, do not alter disease progression. Novel drug design studies have focused on the classical ChE inhibitor, (-)-physostigmine, producing alterations in chemical composition and three-dimensional structure, which may offer an improved therapeutic index. The phenylcarbamate derivative, (-)-phenserine, is a selective, non-competitive inhibitor of acetylcholinesterase (AChE). In vivo, (-)-phenserine produces rapid, potent, and long-lasting AChE inhibition. As a possible result of its preferential brain selectivity, (-)-phenserine is significantly less toxic than (-)-physostigmine. In studies using the Stone maze paradigm, (-)-phenserine has been shown to improve cognitive performance in both young learning-impaired and elderly rats. In addition to reducing inactivation of acetylcholine in the brain, (-)-phenserine appears to have a second mode of action. Reduced secretion of beta-amyloid (Abeta) has been observed in cell lines exposed to (-)-phenserine, occurring through translational regulation of beta-amyloid precursor protein (beta-APP) mRNA via a non-cholinergic mechanism. These in vitro findings appear to translate in vivo into animal models and humans. In a small study of patients with AD, (-)-phenserine treatment tended to reduce beta-APP and Abeta levels in plasma samples. Clinical studies also reveal that (-)-phenserine (5-10 mg b.i.d.) had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks. Further randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)-phenserine in patients with AD are currently ongoing.

Thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. However, the mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide is clinically valuable in the treatment of erythema nodosum leprosum (ENL) and multiple myeloma and effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels and angiogenesis in vivo. This contrasts with its relatively weak effects on TNF-alpha and angiogenesis in in vitro studies and implies that active metabolites contribute to its in vivo pharmacologic action and that specific analogues would be endowed with potent activity. Our focus in the structural modification of thalidomide is toward the discovery of novel isosteric active analogues. In this regard, a series of thiothalidomides and analogues were synthesized and evaluated for their TNF-alpha inhibitory activity against lipopolysacharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), This was combined with a PBMC viability assay to differentiate reductions in TNF-alpha secretion from cellular toxicity. Two isosteric analogues of thalidomide, compounds 15 and 16, that mostly reflect the parent compound, together with the simple structure, dithioglutarimide 19, potently inhibited TNF-alpha secretion, compared to thalidomide, 1. The mechanism underpinning this most likely is posttranscriptional, as each of these compounds decreased TNF-alpha mRNA stability via its 3'-UTR. The potency of 19 warrants further study and suggests that replacement of the amide carbonyl with a thiocarbonyl may be beneficial for increased TNF-alpha inhibitory action. In addition, an intact phthalimido moiety appeared to be requisite for TNF-alpha inhibitory activity.