Volume 85 Issue 19 | pp. 56-60
Issue Date: May 7, 2007

Pharmaceutical Revelations

Medicinal chemists disclose drug candidates for hepatitis, cancer, and other conditions
Department: Science & Technology, ACS News
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Cancer Fighters
The Novartis developers of NVP-BEZ235 include (from left) Pascal Furet, Hans-Georg Capraro, Joseph Brueggen, Garcia-Echeverria, Sauveur-Michel Maira, and Frédéric Stauffer.
Credit: Melanie Krebs
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Cancer Fighters
The Novartis developers of NVP-BEZ235 include (from left) Pascal Furet, Hans-Georg Capraro, Joseph Brueggen, Garcia-Echeverria, Sauveur-Michel Maira, and Frédéric Stauffer.
Credit: Melanie Krebs
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Tumor Team
Key Bristol-Myers Squibb chemistry personnel behind BMS-690514 are (from left) Derek Norris, Harold Mastalerz, Ping Chen, Brian Fink, and Gavai. The poster behind them shows how they think the compound binds to one of its targets, HER1.
Credit: Charlotte Raymond & John Tokarski/BMS
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Tumor Team
Key Bristol-Myers Squibb chemistry personnel behind BMS-690514 are (from left) Derek Norris, Harold Mastalerz, Ping Chen, Brian Fink, and Gavai. The poster behind them shows how they think the compound binds to one of its targets, HER1.
Credit: Charlotte Raymond & John Tokarski/BMS
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Autoimmune Group
Major contributors to the design of Merck's MK-0812 include (from left) Steve Goble, K. Shankaran, Yang, Greg Morriello, Malcolm MacCoss, Gabor Butora, Alex Pasternak, Changyou Zhou, and Chris Moyes.
Credit: Mike Lund
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Autoimmune Group
Major contributors to the design of Merck's MK-0812 include (from left) Steve Goble, K. Shankaran, Yang, Greg Morriello, Malcolm MacCoss, Gabor Butora, Alex Pasternak, Changyou Zhou, and Chris Moyes.
Credit: Mike Lund
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Migraine Combatants
Among the Merck team members who designed MK-0974 are (from left) Theresa Williams, Chris Burgey, Diem Nguyen, Sam Graham, Tony Shaw, Paone, James Deng, and Joe Vacca.
Credit: Susan Alderfer
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Migraine Combatants
Among the Merck team members who designed MK-0974 are (from left) Theresa Williams, Chris Burgey, Diem Nguyen, Sam Graham, Tony Shaw, Paone, James Deng, and Joe Vacca.
Credit: Susan Alderfer
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IN CASE YOU haven't noticed, pharmaceutical industry scientists can occasionally be just a teeny bit secretive about their research.

But each year at the spring American Chemical Society national meeting, drug company researchers get a chance to shine a light on their discoveries. This year, six scientists from five companies took that opportunity.

They revealed previously undisclosed structures of agents for hepatitis C, cancer, autoimmune and inflammatory conditions, incontinence, and migraine headaches that are currently in clinical trials. They spoke at the Division of Medicinal Chemistry symposium "First-Time Disclosure of Clinical Candidates," organized by Andrew W. Stamford, director of medicinal chemical research at Schering-Plough Research Institute, Kenilworth, N.J.

This year's session, attended by more than 800 scientists, "once again highlighted the creativity and innovation of medicinal chemists targeting diseases across a broad range of therapy areas," Stamford said. "One can hope that at least some, if not all, of these newly disclosed entities will ultimately become approved agents, to the benefit of their intended patient populations."

One of the structures publicly revealed for the first time was the hepatitis C medication GSK625433. It was developed by David Haigh, manager of infectious diseases medicinal chemistry at GlaxoSmithKline, Stevenage, England, and coworkers.

Hepatitis C is a liver infection caused by hepatitis C virus (HCV), a single-stranded RNA virus. "HCV truly is a global health problem," Haigh said. "It's estimated that there are somewhere in the region of 170 million carriers worldwide, with 3 million to 4 million new infections each year. The virus is responsible for 40–60% of all liver disease and is the major cause of liver transplants in the Western world."

HCV is transmitted primarily through contaminated blood and blood products. The rate of disease progression is highly variable, but most patients remain symptom-free for an extended period. Aerosmith singer Steven Tyler recently revealed that he was treated successfully for an asymptomatic case of hepatitis C. But many patients eventually progress to symptomatic hepatitis and thence to fibrosis, cirrhosis, liver cancer, and death.

The current gold standard for hepatitis C treatment is a combination of polyethylene glycol-derivatized (PEGylated) interferon-α plus ribavirin, Haigh noted. That regime can eliminate the condition in some patients, he said, if they can maintain the treatment for the six- to 12-month period necessary to clear the virus.

Unfortunately, PEGylated interferon-α and ribavirin therapy has many side effects, so patient compliance is a significant challenge. And the treatment is effective only in about half of patients with HCV genotype 1, the most common form of the virus, Haigh noted. New and better medicines are thus being urgently sought.

Haigh and coworkers directed their drug discovery efforts at virally encoded HCV polymerase. HCV polymerase is essential for viral replication; because it has no mammalian equivalent, researchers believe it would be a good target for selective inhibitory drugs.

HCV genotype 1 has two subtypes, 1a and 1b. The GlaxoSmithKline team had previously identified a series of acylpyrrolidines as potential HCV polymerase inhibitors. The compounds showed good activity against type 1b but had weak potency against 1a, the dominant form of the virus in the U.S. So the researchers aimed to design broader-spectrum compounds that would inhibit both strains effectively.

They used structure-based drug design to optimize the compounds' activity and bioavailability (ability to be absorbed). The result was GSK625433, a highly potent and selective inhibitor of type 1a and 1b HCV polymerases with good activity in cell-based assays. The compound exhibited good pharmacokinetics (absorption, distribution, metabolism, and excretion properties) in preclinical animal tests, and it is currently in Phase I trials.

Meanwhile, Carlos Garcia-Echeverria, executive director of oncology drug discovery at the Novartis Institutes for BioMedical Research, in Basel, Switzerland, and coworkers were developing protein kinase inhibitors for use in cancer treatment. They were trying to identify moderators of the phosphatidylinositol-3-kinase/protein-kinase-B (PI3K-PKB) cell signaling pathway, which plays an important role in controlling cell growth, proliferation, and survival. On the basis of epidemiological data, "it is reasonable to predict that moderators of the PI3K-PKB pathway should have broad antitumor activity against solid tumors," Garcia-Echeverria said.

Starting from a previous lead, the researchers identified a lead compound that inhibits PI3K and another kinase in the pathway. They then used structure-based drug design to improve its efficacy and selectivity toward PI3K. The fruit of their efforts was the imidazoquinoline derivative NVP-BEZ235. The compound potently inhibited the proliferation of a broad panel of tumor cell lines by specifically blocking PI3K enzymatic activity.

In animal models of human cancer, the compound was well-tolerated when administered orally. It caused tumors to stop growing or to regress, and it enhanced the efficacy of other anticancer agents when used in combination with them. "We selected NVP-BEZ235 as our first development candidate for this project, and clinical trials began in December 2006," Garcia-Echeverria said.

At Bristol-Myers Squibb Research & Development, Princeton, N.J., senior principal scientist for oncology chemistry Ashvin V. Gavai and coworkers were also pursuing an anticancer agent. They aimed to inhibit signaling by the growth factor receptor tyrosine kinases HER1 and HER2 and by VEGFR2 kinase (vascular endothelial growth factor receptor-2 kinase). HER1, HER2, and VEGFR2 have been implicated in a variety of tumors, including lung, colon, breast, bladder, and ovarian cancers, as well as squamous carcinoma of the head and neck.

Bristol-Myers Squibb already has a clinical candidate that inhibits HER1 and HER2 selectively. Gavai and coworkers hoped to develop agents that had improved potency against HER1 and HER2 and also had VEGFR2 kinase inhibitory activity. They identified a series of pyrrolotriazine prospects and used crystallography, modeling, and structure-activity studies to optimize the compounds' potency and pharmaceutical properties. BMS-690514 emerged from this effort.

As intended, BMS-690514 inhibits HER1, HER2, and VEGFR2 kinase signaling. The compound produced excellent responses against a number of HER1- and HER2-dependent human breast, gastric, colon, and lung cancers when administered orally to mice. In animal studies, it was well-tolerated and effective at relatively low doses, Gavai said. Phase I clinical trials have begun.

While Gavai's team focused on cancer, Director of Medicinal Chemistry Lihu Yang and coworkers at Merck Research Laboratories, Rahway, N.J., were busy discovering a new autoimmune disease and anti-inflammatory therapeutic. The compound they designed, MK-0812, blocks signaling at CCR2 (chemokine receptor 2), a receptor on blood cells. Previous research has suggested that CCR2 antagonism (blocking the receptor to inhibit its activation) could be a viable approach for treating autoimmune and inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, and atherosclerosis.

Structure-activity studies of an initial screening hit and subsequent medicinal chemistry efforts by Yang and coworkers led them to MK-0812. This potent and selective CCR2 antagonist demonstrated favorable pharmacokinetics in preclinical studies and good efficacy in animal models. In Phase I clinical trials, MK-0812 showed excellent pharmacokinetic profiles and was safe and well-tolerated. In Phase II trials for rheumatoid arthritis, it did not prove any better than a placebo; however, it is currently in Phase II trials for multiple sclerosis.

Across the Atlantic, meanwhile, Gavin A. Whitlock, project leader in the genitourinary therapeutic area at Pfizer Global Research & Development, Sandwich, England, and coworkers aimed their drug discovery efforts at stress urinary incontinence. SUI is loss of urine in the absence of voluntary bladder contraction. If someone with SUI exercises, coughs, or sneezes, they can involuntarily expel urine. The condition can be debilitating and can significantly impair quality of life.

Currently, around 10 million people suffer from SUI in the U.S.; most are female. Risk factors for the condition include pregnancy and childbirth, age, and menopause.

At present, no medicines in the U.S. are approved for SUI treatment. The Eli Lilly & Co. drug duloxetine is an approved SUI therapy in Europe, but it is approved in the U.S. for depression, not for SUI. In addition, duloxetine's efficacy is limited, Whitlock noted, so there remains a significant unmet medical need for new treatments.

Optimizing the potency, selectivity, metabolism, blood-brain barrier penetration, and pharmacokinetics of a novel series of pyrrolidine structures led Whitlock and coworkers to a compound called PF-184298. The agent is a potent inhibitor of the reuptake of secreted serotonin and noradrenaline neurotransmitter molecules in nerve cells.

PF-184298 manifested excellent efficacy in an animal model of SUI. In Phase I trials, it has so far been well-tolerated by patients and has exhibited good pharmacokinetics, with a potential for once-daily dosing. Whitlock notes that its ability to inhibit reuptake of both serotonin and noradrenaline suggests that the compound also has the potential to treat conditions like depression and nerve pain, in addition to SUI.

Back in the U.S., migraine headache was a condition that research fellow Daniel V. Paone and coworkers at Merck Research Laboratories, in West Point, Pa., aimed to treat. Migraine is a type of headache that generally lasts from four to 72 hours. It causes moderate to severe pain, often accompanied by nausea and oversensitivity to light and sound. About 13% of the U.S. population suffers from migraines; about 5% have migraine attacks 18 or more days per year, and about 1% have one per week.

TRYPTAMINE-BASED agents that activate 5-hydroxytryptamine type 1B and 1D receptors are generally perceived to be the most effective treatments for migraine attacks, Paone said. But use of such agents is limited because they constrict blood vessels and are thus not recommended for patients with cardiovascular disease, he added.

"There is a large potential here to help people who are not responding to or who are not taking the standard therapy," he said. And there is a need for agents with better efficacy and safety profiles than current migraine medicines, he noted.

Paone and his coworkers aimed to find a new drug that blocks the ability of calcitonin gene-related peptide (CGRP) to activate its receptor. CGRP is a 37-amino-acid neuropeptide that has been implicated in migraine. The idea was that agents that inhibited activation of the CGRP receptor might block pain transmission and nerve-related inflammation, as well as regulate cerebral blood flow, thus relieving migraine pain and associated symptoms without causing adverse cardiovascular effects. An earlier clinical compound with such activity had been shown to be effective in treating acute migraine attacks, but it was not orally bioavailable.

Paone and coworkers carried out a high-throughput screen for CGRP binding and identified some lead compounds. Truncation of one of the leads followed by extensive structure-activity studies enabled them to identify potent derivatives with improved oral bioavailabilities. Further refinement resulted in the CGRP receptor antagonist MK-0974.

The agent showed efficacy in a dermal-blood-flow assay in rhesus monkeys and is currently in clinical trials for the treatment of acute migraine. Initial human safety trials demonstrated that MK-0974 is generally safe and well-tolerated and has favorable pharmacokinetic properties. Phase II studies showed that it could provide two to 24 hours of sustained pain relief. Phase III trials for migraine treatment started recently. Pending results of that trial, Merck anticipates filing for Food & Drug Administration approval in 2009.

Asked to comment on the raison d'être of the annual first-disclosures sessions, Pfizer's Whitlock explained that discovering new drug candidates "is a very difficult business," with many properties to get right before compounds can go into human testing. "This is a process that can take many years, is often likely to fail, and requires scientists to come up with innovative solutions to problems," he said.

The first-disclosures symposia highlight the central role that medicinal and synthetic organic chemists play in this process. "Without chemists designing new molecules and making them in a lab, new medicines would not be discovered to treat debilitating and life-threatening diseases," Whitlock said.

Merck's Paone added that the symposia "bring to light the most exciting and cutting-edge research in the pharmaceutical industry and provide learning opportunities for the scientific community. The findings reported at these sessions spur further research, and ultimately society will benefit."

 
Chemical & Engineering News
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