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Symposium Tells The Chemistry Stories Behind Drug Candidates

ACS Meeting News: Traditional session described potential drugs for schizophrenia, insomnia, hepatitis C, and HIV

by Carmen Drahl , Lisa M. Jarvis
March 31, 2014 | A version of this story appeared in Volume 92, Issue 13


The American Chemical Society national meeting’s “First-Time Disclosures” session usually marks the public debut for four or five structures of drug candidates, which are molecules wending their way through human clinical trials. In Dallas this month, however, only one new structure saw the light of day. The other talks in the traditional Division of Medicinal Chemistry session covered structures already made public.

More on this story

Disclosing Drug Candidates

Session moderator Lorin A. Thompson of Bristol-Myers Squibb told C&EN to expect at least four disclosures for this fall’s San Francisco meeting. More important than how many talks a particular session has, he says, are the medicinal chemistry lessons learned from the talks. “This symposium has the kinds of stories every chemist wants to hear,” he says.

Jump to Topics:
- AQW051
- MK-1064




Konstanze Hurth, a senior investigator in global discovery chemistry at the Novartis Institutes for BioMedical Research, in Basel, Switzerland, unveiled the experimental schizophrenia drug AQW051. The molecule targets the α7 nicotinic acetylcholine receptor.

People with schizophrenia experience several types of symptoms. Newer schizophrenia drugs, called atypical antipsychotics, ease certain symptoms, such as hallucinations and disorganized speech. They have almost no effect, however, on so-called cognitive symptoms, which include impairments to memory, problem solving, attention, and decision making.

Exposure to nicotine improves some of those cognitive symptoms, so many schizophrenia patients smoke. “It’s a type of self-medication,” Hurth said in Dallas. Drugmakers, therefore, are trying to mimic nicotine’s cognitive effects without the deleterious effects of cigarettes. To do so, companies have focused on α7 nicotinic receptors, which can be found in areas of the brain important for learning and memory.

This has been far from an easy road, however. In December, the biotech company Targacept ended development of TC-5619, the most prominent predecessor to AQW051, after a string of disappointments. The first major blow came when Targacept’s development partner, AstraZeneca, returned the rights to the drug in 2011. A year later, TC-5619 flunked a midstage study for treatment of attention deficit hyperactivity disorder. The knockout punch came in December, when Targacept reported that TC-5619 failed to show efficacy in a Phase II study for treatment of schizophrenia.

In Dallas, Hurth set out to demonstrate that AQW051 could overcome its forebears’ shortcomings. Her team’s early benchmark was a molecule called JN403. Although JN403 was selective for α7 over related receptors and improved rodents’ learning and memory, it raised red flags in terms of cardiac safety.

Novartis chemists searched for safer alternatives with high-throughput screening and evaluated the 11 chemical families that came up as hits. AQW051 is a quinuclidine ether. Hurth’s team learned that making adjustments to the molecule’s phenyl ring had strong effects on its selectivity and druglike properties.

AQW051 was highly selective for the α7 nicotinic receptor and also had a good cardiac safety profile.

In rodents, AQW051 quickly penetrated the blood-brain barrier. Once inside the brain, the molecule improved the animals’ performance on memory tests.

Credit: Novartis
The chemistry team behind drug candidate AQW051 includes Mathias Frederiksen (from left), Dominik Feuerbach, Hurth, Thomas J. Troxler, and Joachim Nozulak.

Data from Phase I clinical trials, which tested AQW501’s safety in young and elderly healthy volunteers, led the Novartis team to conclude that the molecule is safe: The team saw no abnormalities in electrocardiograms. The compound is suitable for once-per-day dosing, Hurth said in Dallas. Multiple Phase II studies are ongoing to test AQW051’s efficacy at treating cognitive impairment in schizophrenia patients.



Making a medication selective for one protein may be a way of maximizing its benefits, but sometimes targeting multiple proteins ends up being the best option.

Merck Research Laboratories is considering all of its options with a potential new class of sleep aids. In Dallas, Associate Principal Scientist Anthony J. Roecker of Merck’s West Point, Pa., site described MK-1064, a selective orexin 2 receptor antagonist for treatment of insomnia. Merck published MK-1064’s structure in December (ChemMedChem 2013, DOI: 10.1002/cmdc.201300447).

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. A Food & Drug Administration advisory panel last July recommended approving a low-dose form of the drug. The agency held off on granting a formal green light until Merck could produce studies showing that the company can manufacture the 10-mg version consistently and safely. Higher doses—namely 30- and 40-mg versions of the pill—were not deemed safe enough for approval.

Merck has finished those additional studies and last month submitted the new data to FDA.

Orexin receptor antagonists are possible alternatives to sleeping pills on the market. Most of these, including Ambien (zolpidem), act on γ-aminobutyric acid receptors in the brain. Although effective, the drugs have side effects including next-day sedation, which prompted FDA to cut recommended dosages in Ambien’s case.

Orexin peptides promote wakefulness, so blocking their actions on orexin receptors might offer relief from insomnia. Two types of orexin receptors reside in the brain; studies suggest that the orexin 2 receptor plays the primary role in wakefulness.

Early orexin 2 receptor antagonists, including Merck’s, weren’t selective enough for researchers to evaluate their effectiveness. Among other issues, some compounds were substrates for pump proteins, which flushed them from their intended site of action in the brain.

Roecker and his colleagues found MK-1064 by first balancing lead molecules’ potency, selectivity, and accessibility to the body when taken orally. Adjustments such as installing polar functionalities and blocking potential metabolic hot spots led to MK-1064.

MK-1064 passed safety tests in rats and dogs. Animal tests also helped the research team conclude that it could mimic the sleep effects of a dual antagonist such as suvorexant with a selective orexin 2 receptor antagonist.

In Phase I human clinical trials, which are now completed, researchers determined MK-1064 to be well tolerated at doses of up to 250 mg. The compound’s half-life is 1.6 to 4.0 hours, a desirable range for a possible sleep aid.

Roecker told attendees to expect more disclosures about MK-1064’s biological effects in summer 2014. Asked whether Merck is still actively pursuing MK-1064, a company spokeswoman told C&EN that Merck does not disclose development plans for early compounds.


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