Liveblogging First-Time Disclosures of Drug Structures from #ACSDallas

Watch this space, chem-keteers.

Starting at 2PM Central time TODAY, I’ll be continuing my spring tradition of live-blogging the public unveiling of drug structures from ACS Dallas.

This spring’s symposium, unfortunately, only contains one true ‘reveal’ – schizophrenia drug candidate AQW051, from Novartis. The other structures are already public. (Three were covered at prior ACS meetings and are part of a ‘where are they now’ talk). I’ve included vintage hand-drawn structures to refresh our collective memories.


BMS-663068 – first presented at ACS Anaheim


asunaprevir– first presented at ACS Fall 2009 (not liveblogged)


BMS-791325- first presented at ACS San Diego


MK-1064 – structure published in December 2013


UPDATE 12:00PM Central time- screengrab of the afternoon’s program

ACS Medi first disclosures spring 2014

1:40PM – grabbed a seat in the second row, by a power outlet. Wifi seems to be behaving. May the liveblogging commence! If you’re on Twitter, watch #ACSMEDI and #ACSDallas hashtags.

AQW051 structure

Company: Novartis Institutes for BioMedical Research
Meant to treat: cognitive impairment associated with schizophrenia (ie, impairment to memory and decision-making)
Mode of action: partial agonist at the alpha7 nicotinic acetylcholine receptor
Medicinal chemistry tidbit: Novartis started with a lead called JN403, but cardiotoxicity issues limited progress with this molecule. high throughput screening led to 11 chemical families, including quinuclidine ethers, which led to AQW051. Hurth’s team noticed that changes to the molecule’s phenyl moiety made big differences in selectivity for related receptors and other parameters.
Status in the pipeline: Phase II clinical trials
Related documents: WO2007068476, WO2007068475, WO2006005608, WO2005123732, WO2004022556; Bioorg. Med. Chem. Lett. 2009, 1287-1291


MK-1064 (see above for structure)
Company: Merck Research Laboratories
Meant to treat: insomnia
Mode of action: selective orexin 2 receptor antagonist
Medicinal chemistry tidbit: MK-1064 is a more selective version of Merck’s dual-orexin receptor antagonist suvorexant, which after setbacks is on the cusp of reaching the market.
Research suggests that orexin 2 plays the primary role in wakefulness, so a more selective antagonist could provide relief from insomnia. Merck’s early orexin 2 receptor antagonists were not sufficiently selective and had metabolic issues (eg, pump proteins). Lowering molecular weight and blocking metabolic hot-spots led to MK-1064
Status in the pipeline: Completed Phase I clinical trials
Related documents: ChemMedChem 2014, DOI: 10.1002/cmdc.201300447 ; BMCL 2013, 23, 6620


asunaprevir and BMS-791325 (now has generic name – beclabuvir) (structures above)
Company: Bristol-Myers Squibb
Meant to treat: hepatitis C virus
Mode of action: asunaprevir inhibits viral NS3 protease; beclabuvir inhibits viral RNA polymerase, however, it is not a nucleoside mimic and so binds outside the polymerase active site
Status in the pipeline: Phase III clinical trials
Among several clinical tests discussed in Dallas, asunaprevir and beclabuvir were tested as part of a triple-drug cocktail with daclatasvir, BMS’s experimental NS5A inhibitor. Phase 2b study-The triple regimen dosed for 12 weeks achieved cure rates of up to 94%.
Related documents: Gastroenterology 2014, DOI: 10.1053/j.gastro.2013.10.057; New Engl. J. Med. 2012, DOI: 10.1056/NEJMoa1104430 ; J. Med. Chem. 2014, DOI: 10.1021/jm500297k; J. med. Chem. 2014, DOI: 10.1021/jm4016894


Company: Bristol-Myers Squibb
Meant to treat: HIV-1
Mode of action: BMS-663068 is a prodrug. Once activated it binds directly to the HIV virus to prevent viral attachment to and entry into immune cells.
Status in the pipeline: Phase III clinical trials
In a Phase 2b clinical trial, BMS-663068 showed similar response rates at tamping down HIV infection to a combination of Reyataz, BMS’s antiretroviral protease inhibitor, and AbbVie’s Norvir, which blocks human cytochrome P450 enzymes to extend Reyataz’s half-life.
Related documents: J. Med. Chem. 2013, 1656; J. Med. Chem. 2012, 2048 ; CROI Meeting, 2014, Abstract 86

That’s it, folks. THANKS to everyone for following along.

Author: Carmen Drahl

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