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Pharmaceuticals

Drug Candidates' Big Reveal

ACS Meeting News: Medicinal chemists unveil potential drugs for brain, autoimmune, liver ailments

by Carmen Drahl
April 12, 2010 | A version of this story appeared in Volume 88, Issue 15

ALZHEIMER'S ALLIES
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The team behind SAM-531 stands with the entire medicinal chemistry group at the former Wyeth site in Princeton, N.J. Robichaud is in the third row, third from the left of the Wyeth sign.
The team behind SAM-531 stands with the entire medicinal chemistry group at the former Wyeth site in Princeton, N.J. Robichaud is in the third row, third from the left of the Wyeth sign.

Pharmaceutical company chemists converged on San Francisco last month, packing into a ballroom at the American Chemical Society's national meeting to hear the chemistry story behind six experimental drugs. The event, an annual session at the ACS meeting, represents a rare opportunity for chemists in industry to share their research stories and learn lessons from each other.

Session organizer Albert J. Robichaud, vice president of chemistry at Danish drugmaker H. Lundbeck, introduced each of the speakers in the Division of Medicinal Chemistry's "First-Time Disclosures of Clinical Candidates" symposium, which was sponsored by Gilead. Each presenter unveiled for the first time the structure of a drug candidate. Attendees learned about possible drugs for Alzheimer's disease, schizophrenia, rheumatoid arthritis, hepatitis C, and insomnia.

Although the symposium showcased success stories from medicinal chemists, the drug industry has been going through a tumultuous time in recent months. Robichaud and speaker John K. Walker are no longer employed with Pfizer, the company they represented at the session. And development for one of the six drug candidates has recently been discontinued.

Robichaud shared the story of Pfizer's SAM-531, a potential treatment for the cognitive deficits in diseases such as Alzheimer's. Discovery and development of this candidate, also known as WAY-262531, began at Wyeth.

More than 5 million Americans have Alzheimer's, according to the Alzheimer's Association. One characteristic of the disease is that patients gradually lose acetylcholine and glutamate neurotransmitter activity, which intensifies problems with learning, memory, and reasoning. Drugs on the market can offset those deficits but have side effects such as nausea or diarrhea.

When experiments in rats suggested that blocking 5-HT6, a receptor for the neurotransmitter serotonin, had beneficial effects on cognition, Robichaud and his colleagues were intrigued. The group speculated that hitting this receptor, a different target from those used by the marketed drugs, could lead to drugs with fewer side effects, Robichaud explained. At the time, the team was already working to make activators of this receptor for other uses, he said. Some of the molecules they'd already made could block the 5-HT6 receptor. So they decided to explore those molecules further.

The team adapted heterocycles that resemble serotonin to make them block the 5-HT6 receptor selectively and endow them with druglike properties (J. Med. Chem. 2010, 53, 2521). They soon noticed that potent antagonists had a few things in common—a sulfonamide moiety and a basic amine. "We came to realize that the heterocycle was merely a template to hold the basic amine and the arylsulfonyl substituents in a position that the receptor likes," Robichaud said. So the team further modified the heterocycles, yielding molecules that could reach the brain more efficiently and had fewer side effects in animal tests. Eventually, the effort produced SAM-531.

Behavioral and biochemical tests in rodents show that SAM-531 indirectly boosts levels of both glutamate and acetylcholine neurotransmission. And the animal tests indicate that SAM-531 is likely to have fewer side effects in people than marketed drugs do, although only clinical trials will tell for sure, Robichaud said. The experimental drug is administered orally and is in Phase IIb clinical trials in people with mild to moderate Alzheimer's. In the trials, researchers will examine biomarkers and look for indications that the drug will benefit Alzheimer's patients.

AstraZeneca's Thomas R. Simpson, associate director of medicinal chemistry located in Wilmington, Del., revealed the structure of AZD2624, a drug candidate that reached Phase II clinical trials in patients with schizophrenia before being discontinued in 2009.

Schizophrenia affects about 1% of Americans over the age of 18, according to the National Institute of Mental Health. Patients with the disease typically take drugs with a mixture of activities, including blocking dopamine D2 receptors in the brain. But the drugs have side effects and don't treat all of schizophrenia's symptoms.

Adjusting dopamine levels in the brain by an indirect mechanism could address some of those issues, Simpson explained. He and his coworkers learned that blocking the neurokinin-3 receptor (NK3r), a G-protein-coupled receptor in the brain, might help, so they decided to pursue this strategy.

Simpson and colleagues took inspiration from talnetant, a quinoline NK3r blocker developed by GlaxoSmithKline that reached Phase II clinical trials for schizophrenia before being discontinued. They sought to improve talnetant's solubility, among other properties. One of the team's more promising quinolines had a sulfonate ester substituent that was susceptible to hydrolysis. Replacing the sulfonate ester with an alkylsulfonylamino group not only eliminated the hydrolysis problem but also led to improvements in solubility. This fine-tuning led the AstraZeneca team to AZD2624.

SCHIZOPHRENIA SQUAD
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The AstraZeneca scientists who discovered AZD2624 are (from left) Hui Xiong, James M. Woods, John P. McCauley, Simpson (seated), Jeffrey S. Albert, Gerard M. Koether, Lindsay Hinkley, Cristobal Alhambra, and James Kang.
The AstraZeneca scientists who discovered AZD2624 are (from left) Hui Xiong, James M. Woods, John P. McCauley, Simpson (seated), Jeffrey S. Albert, Gerard M. Koether, Lindsay Hinkley, Cristobal Alhambra, and James Kang.

In animal tests, AZD2624 led to an increase in dopamine levels in the brain, an effect that's thought to be helpful for treating schizophrenia. In Phase I clinical trials in healthy people, high doses of AZD2624 had a significant side effect—reductions in testosterone levels. So a Phase II clinical trial was set up to evaluate the efficacy of a dose that didn't have that side effect.

That dose didn't lead to robust improvements in schizophrenia symptoms in the Phase II trial, so AstraZeneca discontinued development of AZD2624 in 2009.

Although AstraZeneca recently announced it is exiting research in the schizophrenia area (C&EN, March 8, page 19), it is exploring AZD2624's possible use as a neuroendocrine modulator and other avenues in which it might benefit patients.

Also at the San Francisco session, Paul J. Coleman, senior director of medicinal chemistry at Merck & Co., in West Point, Pa., described MK-4305, the last of the symposium's three drug candidates designed to reach the brain. The experimental therapy is in clinical trials for treatment of insomnia.

Insomnia periodically affects 50% of adults, Coleman said at the session. Most sleeping pills on the market adjust the activity of γ-aminobutyric acid (GABA) receptors in the brain, he explained. But GABA-targeted drugs aren't very specific. They shut down neuronal activity in the brain, not just in areas regulating sleep and waking, he said. In addition, the drugs can cause memory disturbances and next-day sedation.

Merck set out to develop a drug that would help insomniacs experience something closer to natural sleep. The company focused on blocking the activity of orexin receptors, which are found on neurons that project from the hypothalamus of the brain. Normally, these receptors respond to peptides called orexins, which contribute to wakefulness. Absence of orexins or their receptors has been linked to narcolepsy, a disorder in which patients spontaneously fall asleep. Successful Phase II clinical trials conducted by Actelion Pharmaceuticals and GlaxoSmithKline on their orexin receptor blocker, almorexant, suggest that blocking orexin receptors could be a viable approach for treating insomnia.

INSOMNIA GROUP
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The Merck medicinal chemists who designed and synthesized MK-4305 are (from left) Michael Breslin, Swati Mercer, John Schreier, Coleman, Chris Cox, and Anthony J. Roecker.
The Merck medicinal chemists who designed and synthesized MK-4305 are (from left) Michael Breslin, Swati Mercer, John Schreier, Coleman, Chris Cox, and Anthony J. Roecker.

Coleman and his colleagues looked into several different classes of molecules as orexin receptor blockers and decided to pursue seven-membered-ring heterocycles called diazepanes (ChemMedChem 2009, 4, 1069). They focused on finding molecules with the right lipophilicity, so they would reach the brain but not be metabolized in undesirable ways. The team also hunted for molecules that would start working quickly but would not stick around for so long that people would feel residual effects in the morning. The team eventually discovered MK-4305, a potent blocker of two orexin receptors.

In rats, MK-4305 promoted sleep in a dose-dependent manner and increased the time rats spent in various sleep stages. The team didn't see instances of cataplexy, the muscle weakening sometimes associated with narcolepsy, in preclinical studies of MK-4305. The drug candidate is administered orally and is in Phase III clinical trials for insomnia.

Describing efforts to treat hepatitis C, Paul M. Scola, a senior principal scientist at Bristol-Myers Squibb, in Wallingford, Conn., disclosed the structure of BMS-650032. Hepatitis C affects 3% of the world's population, and the disease "is insidious in the sense that the initial infection is somewhat benign, with flulike symptoms," Scola said. Hepatitis C causes 10,000 deaths per year in the U.S. alone and is the leading cause of liver transplants.

Physicians treat hepatitis C with a combination of ribavirin and polyethylene glycol-derivatized (PEGylated) interferon-α. However, this therapy has side effects, such as depression. In addition, it isn't equally effective in all patients.

Leaders in the field contend that no single antiviral agent will be sufficient to treat hepatitis C and that a cocktail of two or more drugs will be necessary, Scola said. One component of BMS's strategy is blocking the NS3 protease, a serine protease that is essential for viral replication.

HEPATITIS TEAM
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Bristol-Myers Squibb medicinal chemists behind BMS-650032 include (from left) Brian Venables, Alan Wang, Ny Sin, Sing-Yuen Sit, Yan Chen, Stanley D'Andrea, Li-Qiang Sun, Nicholas Meanwell, Zhizhen Zheng, Scola, and Jie Chen.
Bristol-Myers Squibb medicinal chemists behind BMS-650032 include (from left) Brian Venables, Alan Wang, Ny Sin, Sing-Yuen Sit, Yan Chen, Stanley D'Andrea, Li-Qiang Sun, Nicholas Meanwell, Zhizhen Zheng, Scola, and Jie Chen.

The BMS team began by examining X-ray structural data about how known peptidic inhibitors interact with NS3. From that information they developed their signature element—an acylsulfonamide group. This group makes important binding contacts near the active site of the protease. Replacing a carboxylic acid with the acylsulfonamide boosted a tripeptide's ability to block NS3's activity by greater than 100-fold. Further adjustments increased their compounds' druglike properties and ability to reach the liver.

BMS's first NS3 blocker to reach clinical trials for hepatitis C, BMS-605339, looked promising but was discontinued because some patients experienced a slight reduction in heart rate. The team went back to the lab and developed a rabbit heart model to learn more about the candidate's cardiovascular effects and how to avoid them. In the end, subtle adjustments to BMS-605339's isoquinoline ring resolved the cardiovascular issues, leading to BMS-650032.

BMS-650032 has potent antiviral activity in hepatitis C-infected patients, is well tolerated, and has a safety profile similar to that of a placebo, Scola said. The compound is administered orally and is in Phase II clinical trials.

AUTOIMMUNE CREW
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The Lexicon team behind LX2931 includes (from left) Jeff Bagdanoff, Marianne Carlsen, Mike Gardyan, Augeri, Simon Baugh, James Tarver, Tad Jessop, Kristen Terranova, and Joe Barbosa. Ken Carson is not pictured.
The Lexicon team behind LX2931 includes (from left) Jeff Bagdanoff, Marianne Carlsen, Mike Gardyan, Augeri, Simon Baugh, James Tarver, Tad Jessop, Kristen Terranova, and Joe Barbosa. Ken Carson is not pictured.

Two speakers revealed potential new drugs for autoimmune diseases such as rheumatoid arthritis. John K. Walker discussed Pfizer's experimental drug, PF-04629991, and David Augeri, director of medicinal chemistry at Lexicon Pharmaceuticals, in Princeton, N.J., told the story of LX2931 and LX2932.

Rheumatoid arthritis affects 1.3 million Americans, according to the Arthritis Foundation. The disease "keeps mounting an immune response to certain joints until you get destruction of bone and cartilage," Walker said. Treatments include small-molecule pain relievers and steroids, as well as injectable biologic agents for slowing the disease's progression.

Many of the more effective treatments globally suppress the immune system and leave patients susceptible to infections, so a more target-specific therapy would be helpful. Both the Lexicon and Pfizer teams designed molecules that adjust signaling from sphingosine-1-phosphate (S1P), a lipid that controls the distribution of white blood cells called lymphocytes between the bloodstream and the lymph nodes. The idea behind both companies' candidates is to keep some lymphocytes out of circulation, where they might lead to joint destruction.

The Pfizer team designed molecules that bind to a receptor for S1P. Novartis adopted the same approach in making an experimental multiple sclerosis drug, fingolimod, which is in late-stage clinical trials, Walker said. But fingolimod is not selective for just one S1P receptor, which is thought to be the reason for some of its side effects.

As part of an effort to treat another disease, a team at Pfizer had started working on compounds selective for an S1P receptor called S1P1. Walker and his coworkers fine-tuned molecules from that effort to improve their selectivity and druglike properties. By feeding a compound to a rat and then taking white blood cell counts from blood samples, the team could tell whether their molecules lowered numbers of lymphocytes in circulation.

An aminocyclobutane carboxylic acid moiety proved crucial for activity, Walker said. And adding a chiral methyl group to their compounds slowed the rate at which they were metabolized. These insights led to PF-04629991, which selectively binds to the S1P1 receptor.

The experimental drug was effective in treating a rat with chronic inflammation characteristic of rheumatoid arthritis. PF-04629991 is administered orally and is in Phase I clinical trials, which will evaluate the candidate's safety and dosing.

Instead of binding to a receptor that responds to S1P, Lexicon's drug candidates inhibit S1P lyase, an enzyme that degrades S1P. The goal is the same as that of the Pfizer team—to lower the levels of lymphocytes in circulation, Augeri said in San Francisco.

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Lexicon's work began with its Genome 5000 program, which aims to uncover the functions of 5,000 genes encoding likely drug targets by carefully knocking each one out in a mouse. Mice lacking S1P lyase had lower levels of lymphocytes in circulation and higher levels of S1P inside cells in lymphoid tissue.

From a report in Science (2005, 309, 1735), the Lexicon team learned that THI, a trace component of the food coloring that gives Coca-Cola its caramel tint, has a similar lymphocyte-level-lowering effect on mice. But THI isn't an optimal drug candidate—it is poorly soluble and has a reactive ketone. "Our goal was to come up with an analog that was more stable and more soluble," Augeri said.

Changes to THI's imidazole core and hydroxylated side chain weren't helpful (J. Med. Chem. 2009, 52, 3941). But subtle changes to the ketone made a tremendous difference. Changing the ketone to an oxime gave a stable, soluble compound that became LX2931. And tying up the ketone in a heterocyclic isoxazole ring gave LX2932. LX2931 and LX2932 do not appear to inhibit S1P lyase directly, so Lexicon is exploring the mechanism of both drug candidates.

In rats, both compounds were effective at treating an aggressive model of rheumatoid arthritis. And in a Phase Ia clinical trial on healthy patients, LX2931 led to a dose-dependent decrease in lymphocyte levels in circulation. LX2931 is administered orally and is in Phase II clinical trials, which will evaluate its efficacy in patients with rheumatoid arthritis. LX2932 has completed preclinical testing.

Asked to comment on the significance of the annual first disclosures session, Augeri said the diversity of diseases and targets covered ensure a learning experience for all in attendance. "All of these programs are unique," and each has overcome different challenges to reach clinical trials, he said.

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