Drug Candidate Structures Revealed At #ACSAnaheim The Haystack. Drug Candidate Structures Revealed At #ACSAnaheim

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1 页码,1/8 Back To C&EN ACS Journals C&EN CAS CENtral Science The Haystack Search Home Cleantech Chemistry IYC 2011 Just Another Electron Pusher Newscripts Terra Sigillata The Chemical Notebook The Editor's Blog The Haystack The Safety Zone Transition States Expand» About This Blog March 27th, :03 Drug Candidate Structures Revealed At #ACSAnaheim By Carmen Drahl Posted in Big Pharma, Biotech, Diabetes/Obesity, Meetings, Neurology, Oncology, Small Molecules Tagged: $BMY $CEPH $ELN $LXRX Alzheimer's BMS Bristol-Myers Squibb CEP Cephalon Elan ELND006 HIV irritable bowel syndrome Lexicon LX1031 Merck MK-0893 MRK type 2 diabetes 10 Comments 1PM Pacific: There s one hour left before chemists will pack a ballroom in Anaheim to see potential new drugs structures unveiled for the first time. Watch this space for updates. 2:39PM Pacific: CEP This drug candidate now has a name: irdabisant company: Cephalon meant to treat: deficits in cognition and/or attention in diseases such as Alzheimer s and schizophrenia mode of action: inverse agonist of histamine H3 receptor, which regulates several neurotransmitter pathways involved in cognition, attention, memory medicinal chemistry tidbits: Cephalon s goal was to bring a high quality compound to the clinic to define the utility, if any, of H3 antagonists for these indications. The team studied compounds in this area that failed. Among the things they learned was that several adverse events could be tied to drug candidates lipophilicity. So the team prioritized lipophilicity and other such characteristics in its discovery workflow. status in the pipeline: completing Phase I in the beginning of April 2011,

2 页码,2/8 advancing to Phase II structure coming soon! UPDATED 3/29 with structure: CEP :16PM Pacific: BMS company: Bristol-Myers Squibb meant to treat: HIV mode of action: inhibits HIV attachment to host cells by binding to the viral envelope gp120 protein and interfering with its attachment to host CD4 receptors medicinal chemistry tidbits: potency and getting the drug candidates to reach the bloodstream efficiently were key. Replacing a methoxy group on with heterocycles, such as triazoles, gave a big boost in potency. status in the pipeline: Completed Phase IIa clinical trials. Phase IIb studies are planned for later this year. BMS :24PM Pacific:LX1031 company: Lexicon meant to treat: irritable bowel syndrome

3 页码,3/8 mode of action: blocks a subtype of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, in the gut. medicinal chemistry tidbits: Lexicon started their medchem program with an open mind. They could have made a molecule that was exquisitely selective for the subtype of tryptophan hydroxylase in the gut, they could avoid hitting the other subtype by making their molecule stay out of the brain, or both. They ultimately ended up using the latter strategy, making molecules slightly on the heavy side (above 500 or 550 molecular weight) and adding groups like a carboxylic acid, that tend to keep things out of the brain. status in the pipeline: Completed Phase IIa clinical trials. 5:30PM Pacific: MK-0893 company: Merck meant to treat: type 2 diabetes mode of action: blocks the receptor for the hormone glucagon. Glucagon is released by the pancreas in response to falling glucose levels. medicinal chemistry tidbits: Merck kept several chemical scaffolds in play during this research program. But the team s big breakthrough was adding a methyl group to the benzylic position of a promising compound, which greatly improved potency. This methyl group strategy hadn t worked for previous compound series, but the team revisited it anyway. status in the pipeline: Completed some Phase II trials, according to clinicaltrials.gov ELND006 company: Elan meant to treat: Alzheimer s disease mode of action: blocks gamma-secretase, a key enzyme in the production of amyloid-beta, the peptide behind the plaques that mar Alzheimer s patients brains. medicinal chemistry tidbits: Adding a cyclopropyl group and a trifluoromethyl group enhanced molecules metabolic stability. status in the pipeline: discontinued because of adverse liver side effects unrelated to its mode of action.

4 页码,4/8 5:31PM Pacific: That s all for now, folks. I hope to update with more structure information later. Watch for my full story on this symposium in a mid-april issue of C&EN. Subscribe to this author's posts feed via RSS 10 Comments Ping RSS Mar 27th :03 by Chemjobber Interesting to know how the CF3 is being installed. My guess is resolution, I dunno. Mar 27th :03 by Chemjobber uh, er, that s installed enantioselectively. Mar 27th :03 by Carmen Drahl CJ- I don t recall the talk going into that, although these talks are like getting a drink from a firehose. I ll add a comment if I learn anything more. Mar 28th :03 by CR

5 页码,5/8 Structure of CEP coming anytime soon? Mar 28th :03 by Bob Buntrock Good work, Carmen, keep it coming. I especially found the structure useful including those hand drawn. Done with smart phone snaps, I assume? Mar 28th :03 by Carmen sorry for the delay. I don t think I ll have it up indeed it was. Thanks for the kind words. Mar 28th :03 by kristall36 MK-0893 is no longer in the pipeline (Phase II or later). Mar 29th :03 by Carmen Drahl I guess it is still today on the west coast- got Cephalon structure posted! Thanks for the Mar 29th :03 by CR

6 页码,6/8 Great, thanks! Mar 29th :03 by kristall36 My pleasure. Please keep up the good work! Leave a Reply Name (required) Mail (will not be published) (required) Website Submit Comment Log In Username Password Log In gfedc Remember Me Lost your password? Register The Haystack s Authors Lisa Jarvis Carmen Drahl Lisa Jarvis and Carmen Drahl

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