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-26401
This drug candidate now has a name: irdabisant
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, advancing to Phase II
structure coming soon!
UPDATED 3/29 with structure:
3:16PM Pacific: BMS-663068
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.
meant to treat: irritable bowel syndrome
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
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
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.
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.
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