We examined the levels of retention and utilization of 945 coho salmon (Oncorhynchus kisutch) carcasses released experimentally into seven spawning streams on the Olympic Peninsula, Washington. Most carcasses were retained in the streams and in adjacent forests, few were flushed beyond 600 m. Organic debris caught and held many carcasses. Much of the fish mass was consumed by 22 species of mammals and birds. The distances that carcasses drifted appeared to be related directly to the occurrence of freshets and inversely to debris load and carnivore scavenging. The capacity of many streams and rivers to retain carcasses has probably been reduced by human activities. The importance of coho carcasses to populations of carnivores and to the dynamics of lotic food webs merits additional study.
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.
Fused oxadiazines (3) 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 8r and 8s 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 8s confirm that the oxadiazine series of compounds are potent GSMs. KEYWORDS: Alzheimer's disease, oxadiazine, amyloid precursor protein, γ-secreatase modulator, Notch processing, morpholine A lzheimer's disease (AD) is an age-related neurodegenerative disorder that affects millions of elderly people in the United States. It is estimated that more than 35 million people suffer from AD worldwide, with an annual cost of over $600 billion, and the population may increase to more than 115 million by 2050. 1 Because of clear unmet medical need, both academic and industrial laboratories are working very aggressively to develop therapies to halt or even reverse AD. It is believed that the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated protein τ contributes to AD progression. 2−6 Aβ peptide is formed from a larger amyloid precursor protein (APP) via sequential proteolytic cleavage by β-and γ-secretases (Figure 1). 7 γ-Secretase cleaves the APP Cterminal fragment at multiple sites leading to Aβ peptides of 37−42 amino acids of which Aβ 42 , the more hydrophobic form, is the most amyloidogenic and neurotoxic. Although the molecular mechanism of action remains largely unknown, γ-secretase modulators (GSMs) are believed to act at an allosteric site to shift the predominant site of γ-secretase cleavage toward shorter, nonamyloidogenic peptides (e.g., Aβ 38 ) by selectively inhibiting Aβ 42 formation without blocking overall γ-secretase function. This potentially offers a better selectivity window over γ-secretase inhibitors (GSIs) 8−10 versus, for example, notch processing. 11 From an in vitro point of view, the Aβ total /Aβ 42 ratio can be used to distinguish GSMs from GSIs with a ratio of >10 for GSMs and <3 for GSIs. There are two major classes of GSMs in clinical trials: one is the nonsteroidal antiinflammatory acids (NSAIDs), 12,13 and the other is the nonNSAIDs class such as lactam 1 from Eisai. In our effort in the AD area, we have recently identified multiple structural classes 14−18 of GSMs with good in vitro potency and selectivity. Herein, we repo...
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