Alzheimer’s Meds from Plants: Satori Digs up New Leads
Jul20

Alzheimer’s Meds from Plants: Satori Digs up New Leads

Earlier this week, Satori Pharmaceuticals reported from the 2011 Alzheimer’s Association International Conference two new promising lead molecules, SPI-1802 and SPI-1810. Both block gamma-secretase, one of several enzymes involved in snipping the lengthy amyloid precursor protein down to beta-amyloid, the peptide that makes up the plaques coating the Alzheimer’s brain. A slew of big pharma companies are pursuing compounds that inhibit the enzyme (see here for more on the subject). So, you ask: What’s so new about Satori’s approach? For starters, Satori is trying to be very specific about what their compounds target. The researchers claim their compounds promote selective degradation of a single type of brain plaque – Amyloid β-42, the plaque most commonly associated with the disease – without destroying other, shorter amyloid residues (Aβ-38 and -40) that may actually confer neural health benefits. A Satori patent from June 2010 shows the selective amyloid-destroying  abilities are due to six-ring structures isolated from flowering plants. Who says new drugs aren’t discovered from natural products anymore? The patent literature dug up by our gang suggests that Satori’s leads come from the earth; specifically that they are semisynthetic derivatives of compounds extracted from the roots of black cohosh (snakeroot). Native American and Chinese herbal medicine use preparations of this plant, usually brewed as root teas, to aid muscle cramps and pain associated with menstruation or menopause.  Just a casual glance at Satori’s lead structure evokes phytosterol hallmarks: cyclopropanation at C9-C10 (a precursor to B-ring expansion in compounds like cortistatin A, a sea sponge isolate), a highly oxygenated terpene end chain, and a glycosidic linkage off of carbon 1 (far left), coupled to a typical plant sugar such as arabinose or xylose. A major critique of early Alzheimer’s drugs was that it wasn’t clear they were actually binding to their intended enzyme targets, which could explain some of their disappointing clinical results. Indeed, Eli Lilly this week provided more data confirming semagacestat, its lead gamma-secretase inhibitor, actually worsened rather than ameliorated patients’ conditions. Interestingly, Satori’s lead molecules look nothing like most of the big pharma compounds: Semagacestat is a peptide-linked lactam, while Merck’s lead molecules are iminopyrimidones with heterocycles stapled on. It's still too early to tell if the major structural differences in these new lead compounds will overcome the issues associated with semagacestat. But Satori scientists have one selling point: their compounds do not interfere with Notch, a protein involved in a host of key cell–signaling processes, including helping to control cell differentiation, proliferation, and cell death. It also happens to be a substrate for gamma-secretase. The challenge of blocking gamma secretase without disrupting Notch has caused many drug companies to...

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The Meat Grinder Of Drug Discovery: A Photo Tour of NCI’s Natural Products Repository
Feb28

The Meat Grinder Of Drug Discovery: A Photo Tour of NCI’s Natural Products Repository

no images were found Rare is the chemist whose tools of the trade include a meat grinder and a band saw. But then, the Developmental Therapeutics Program's Natural Products Repository and Support Group at the National Cancer Institute in Frederick, Maryland is no ordinary operation. Researchers at NCI are combing nature for potential anticancer compounds. Over 75,000 specimens, a mix of dried plants and frozen marine organisms, have made their way to Frederick from Vietnam, Palau, and other far-flung locales to be tested for biological activity. Kirk Gustafson, head of the natural products chemistry group at NCI's Molecular Targets Laboratory, was kind enough to show me around. After learning about how natural products were collected in times past for my story this week on a new biodiversity treaty, I wanted to visit NCI's repository. My conversations at Frederick often turned to drug discovery. It's clearly a rough time for the industry, and natural products researchers will emphasize how important molecules from nature have been in the drug discovery pipelines of decades past. Derek Lowe, David Kroll and many other more knowledgeable bloggers than I have talked about drugs that are inspired by (or come directly from) nature, and the shuttering of natural products research facilities in some large pharmaceutical companies. But the rotovaps still hum in Frederick. Their search for potential new drugs from nature is still on. More reading: The US National Cancer Institute’s natural products repository; origins and utility, J. Environ. Monit., 2006, 8, 800 UPDATED March 1: added reference to Developmental Therapeutics Program UPDATED March 1: updated link to biodiversity treaty...

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