Compound 14 has been reported to lower Ap levels in the brains of APP transgenic mice after acute administration (69). Although high concentrations of 13 and 14 were shown to inhibit Notch processing in Drosophila (70), their derivative 15 did not cause any apparent toxicity when administered to APP transgenic mice over 3 months (71). Compound 15 exhibits low nM potency and some selectivity for APP over Notch, suggesting that it may be possible to decrease Ap levels without adversely affecting critical Notch signaling events. Compound 15 as well as certain sulphonamides, exemplified by 16, are candidates for clinical trials (72).
Currently, efforts are being made to find y-secretase inhibitors specific for APP over Notch or other known substrates. Other possible side effects of using y-secretase inhibitors as well as their cross-inhibition with other proteases remain to be examined. In this regard, several y-secretase inhibitors, including 6 and 15, have been recently reported to inhibit signal peptide peptidase (SPP), a multi-pass membrane presenilin-like aspartyl protease (59).
Inhibition of AB Production by Unknown Mechanisms - Several non-steroidal antiinflammatory drugs (NSAIDs), such as indomethacin 17, (S)-ibuprofen 18 and sulindac sulfide 19, have been reported to selectively lower Ap42 levels in mammalian cells and in mice without affecting Notch proteolysis (73). Although the mechanism of action of these compounds is unclear, they have easily become candidates for clinical trials for AD prevention. Also, certain isocoumarin compounds 20 and 21 have been reported to be modest y-secretase inhibitors, which lower Ap in cells without affecting Notch processing (74). However, these compounds do not inhibit y-secretase directly, but through some other unknown mechanism (75).
Conclusion - During the past few years, great progress has been made in identifying new p- and y-secretase inhibitors. Although p-secretase has become a more attractive target for AD treatment because of the lack of evident side effects in knockout mice, the search for effective nonpeptidic compounds has been challenged by the large active site of this protease. Many more potent y-secretase inhibitors have been disclosed with a few being tested in vivo. Although knockout of presenilis is lethal because of elimination of Notch signaling, it may nevertheless be possible to lower y-secretase activity pharmacologically without undue toxicity.
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Chapter 6. Urinary Incontinence: Neuropharmacological Approaches
Matthew O. Fraser, Edward C. Burgard, and Karl B. Thor Dynogen Pharmaceuticals, Inc.
Durham, NC 27713
Introduction - The most remarkable breakthrough in incontinence medicines across the last year was the submission of a New Drug Application to the FDA for duloxetine hydrochloride as a treatment of stress urinary incontinence (for which there are no currently approved medicines in the US). In urge incontinence, reformulations of oxybutynin (e.g. extended release and patch formulations) and other muscarinic cholinergic receptor antagonists continue to dominate the market and late stage clinical development programs. Enterprising clinicians have taken matters into their own hands and applied off label-use of various toxins (such as botulinum toxin A injected into the bladder or urethra and intravesical administration of capsaicin) as they try to find remedies for their patients, but safe, effective, and convenient therapy is obviously needed to compliment the anticholinergics.
This chapter describes the neural reflex pathways that control urine storage and micturition and describes pharmacological targets and drug discovery strategies within the context of these reflexes. However, it does not provide detailed discussions of species differences in drug effects, and the reader should be aware that major differences do exist. For example, the role of 5-HT1A receptors in control of micturition appear to be completely opposite in rat and cat (1). Furthermore, within the same species, drug effects can differ with different stages of development or under various pathological conditions that are accompanied by changes in the neural substrate or receptor expression (2-4). Thus, drug candidates should be studied in various clinically-relevant pathological models and in multiple animal species prior to committing extensive resources toward clinical development.
In some cases, the location of targets is not precisely known because drugs were administered intracerebroventricularly or intrathecally and thus could affect either the sensory or motor component of the reflex. Thus, the site of action is inferred from studies of somatic sensory or motor systems in which the site of drugs' effects have been documented.
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