Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12
Nov02

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition. So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects. Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites. Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns....

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It’s Chemistry Carnival Time!
Sep07

It’s Chemistry Carnival Time!

A few weekends ago, I was with my young boys at our local mall checking out the kids entertainer, Ryan Buckle & Friends: Science you can sing to. Ryan, the singer, intersperses his songs with science demonstrations. We were there fairly early for a Saturday morning, so his audience was small and consisted mostly of toddlers and preschoolers – not the easiest crowd to entertain. Even though Ryan’s songs were fun to listen and dance to, it was the experiments that captured every one’s attention (yep, parents, too). Smoke vortex rings puffed air as they floated past our heads. Water “disappeared” from a cup thanks to a gel powder. And then came my favorite reaction of all time: The Diet Coke-Mentos geyser. Simple, sure, but way fun to do with kids. As the mints hit the soda, disrupting polar attractions between water molecules, even my two-year old was mesmerized by the foam spewing forth from the bottle. In this International Year of Chemistry, it seems only natural that we should pay tribute to our favorite chemical reactions, be they as simple as a soda geyser or as sophisticated as the Diels-Alder. So, come one, come all, to the greatest chemistry blog carnival this fall! A blog carnival? You betcha. A blog carnival is a periodic collection of blog posts written loosely around a single theme that are then aggregated at the host blog. The beauty of the carnival is that we all can come together around our passion whether we're part of a network or not. Big name bloggers and fledgling writers. Dogs and cats, sleeping together. Everyone is welcome at a blog carnival. But why a blog carnival, you ask? Well, our good friends at the Scientific American blog network, led by The Blogfather Bora Zivkovic, put on a great show with last month's Chemistry Day (blogposts are aggregated here). To acknowledge the World Chemistry Congress taking place in Puerto Rico at the time, Scientific American network bloggers and a few folks invited to the SciAm Guest Blog took to discussing issues of chemistry in their respective disciplines. Bora was even kind enough to invite our own Carmen Drahl (post) and David Kroll (post) to contribute. But the theme there was very general. We've decided to narrow the theme field a bit. If you hadn't gathered by now, the theme of this carnival is...Your favorite chemical reaction. I know, I know. You've identified your reaction and written a brilliant post. But you're thinking, now what the Mizoroki-Heck do I do with it? Send a note to cencarnival@gmail.com with the following information: The title of the post The name...

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