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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