Liveblogging First-Time Disclosures From #ACSSanDiego
Mar24

Liveblogging First-Time Disclosures From #ACSSanDiego

Watch this space on Sunday as I cover the public unveiling of five drug candidates' structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific. 1:30PM It's half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order. 2:30PM LX4211 Company: Lexicon Pharmaceuticals Meant to treat: type 2 diabetes Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney Medicinal chemistry tidbits: this drug candidate had Lexicon's chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon's chemists realized they could try something different-- inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1. Status in the pipeline: LX4211 is currently completing Phase IIb trials. 3:00PM BMS-927711 Company: Bristol-Myers Squibb Meant to treat: migraine Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that's been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372's cycloheptane ring while maintaining CGRP activity, leading to BMS-927711. Status in the pipeline: Phase II clinical trials 3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar). 3:53 We're a bit behind schedule but got plenty of good chemistry... GSK2636771 Company: GlaxoSmithKline Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta....

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World AIDS Day Roundup
Dec01

World AIDS Day Roundup

Today is World AIDS Day. Here are some selected tidbits of basic science and business developments in the HIV/AIDS arena that we've covered in 2010. (Some C&EN links are subscriber-only). In May, Belgian scientists reported early results on the path to a new type of antiviral- one that blocks an interaction between HIV integrase, which helps the virus integrate its DNA into that of a human host cell, and a human protein that is critical for this process as well. In contrast, the FDA-approved drug raltegravir interferes with the integrase protein itself. The Belgian scientists' report, which you can read here, does not include tests on humans or animals, but it suggests that the approach of blocking this interaction, rather than going straight for the integrase itself, might be a viable option for AIDS drug development. In June, two independent teams determined what an antibody with unusually potent and broad activity against HIV strains looks like. The teams hoped this information could give a boost to the search for an AIDS vaccine. These results, which you can read here and here, are preliminary and nothing has been tested in animals or people yet. But because an AIDS vaccine would have to generate a stronger immune response to the virus than the body is capable of on its own, any clues as to how to make that immune response stronger (say, with a really powerful antibody) are welcome to scientists. In July, researchers at the International AIDS Conference in Vienna reported that a microbiocidal gel containing 1% tenofovir (brand name Viread), an antiretroviral drug, helped lower the risk of contracting HIV and genital herpes. Unlike the more preliminary work I mentioned earlier, this study was done in human patients. Also in July, Gilead Sciences announced it would close its research site in Durham, NC by the end of this year. Gilead first acquired the site when it bought Triangle Pharmaceuticals in 2003. Triangle scientists' drug discovery efforts had led to Gilead's AIDS drug Emtriva, which won regulatory approval months after Gilead acquired the business. NC-based news outlet the News-Observer had extra details on company history when the news broke: Triangle was one of the Triangle's most promising young drug companies. It was formed in 1995 by a group of former Burroughs Wellcome executives led by the late David Barry, who was a co-inventor of the first major AIDS drug, AZT. Tragedy struck the company in 2002 when Barry died of a heart attack at age 58. And finally, at August's American Chemical Society National Meeting in Boston, David S. Teager, a chemist with the Clinton Health Access Initiative, explained how...

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