Posted by ed_uk on December 16, 2004, at 11:35:04
'Elzasonan is a 5-HT1B/1D receptor antagonist. Animal tests show that the compound hits the autoreceptors, and early human trials showed no big safety problems. It is expected to be an antidepressant with a very rapid onset of action.'
An article from Forbes.com.
Health
A Quick Lift for the Blues
Robert Langreth, 08.11.03A gifted Pfizer chemist may have found the first fast-acting drug for depression.
Unlike almost every other senior chemist at Pfizer's Groton, Conn. research campus, Harry Howard Jr. has no Ph.D. He does have a college degree in chemistry, the first person in his family to even attend college; he went on to get a master's while at Pfizer. His father, a custodian, has a sixth-grade education and his mother, a dietician, didn't finish high school.But Howard more than holds his own against his pedigreed colleagues. He was a leading member of the team that discovered Pfizer's antischizophrenia drug Geodon, having put the final tweak on the molecule to reduce its side effects. But all along Howard has always wanted to design a blockbuster drug he could claim as his own. He is closing in on that goal. His totally new type of antidepressant, now in midstage human trials, has the potential to eliminate one of the biggest weaknesses of Prozac, Zoloft and the like: their agonizingly slow onset of action.
Existing antidepressants can take up to six weeks to kick in. (To be sure, drugs like cocaine and amphetamine are instant mood lifters, but they wear off quickly and leave the patient worse than before.) Howard's new drug, elzasonan, aims to take effect in a week by blocking tiny molecular sensors on brain cells that counteract the effects of existing drugs. If it works, it could be a billion-dollar seller and the biggest advance in fighting depression since Prozac's debut in 1987. The compound may also help treat obsessive-compulsive disorder, against which existing drugs take up to 12 weeks to work.
A faster-acting antidepressant means more than convenience to the 45 million depressed Americans. "It would likely reduce suicide rates and decrease the length of hospital stays for the severely depressed," says Charles Nemeroff, Emory University professor of psychiatry.
Pfizer (nyse: PFE - news - people ) has plenty of company in its dream to market a quicker picker-upper. "Literally every pharma company out there has some idea about how to get early onset," says Pfizer neuropharmacologist Jeffrey Sprouse, team leader for the fast-acting antidepressant program. AstraZeneca and GlaxoSmithKline, among others, have fast-acting molecules in the works.
But Pfizer has a huge store of confidence in the iconoclastic work of the 53-year-old chemist Harry Howard. Most research chemists are like generals playing molecular trench warfare, firing out thousands of new compounds in a grueling advance toward the elusive billion-dollar molecule. Howard is far more selective. He broods in front of the computer most of the day, scanning chemical databases and holding his fire until he has a really good idea. Instead of making wholesale changes to a compound, he usually alters one atom at a time. "Harry is quiet. He thinks and thinks and doesn't let on what he is doing," says Sprouse. "Then he makes just a handful of compounds, and they seem to work."
Fresh out of college, Howard joined Pfizer as a lowly lab assistant in 1974; he was attracted to the idea of manipulating matter on such a small scale. "You are almost playing God," he says. He displayed such a knack for dreaming up compounds that he was promoted to lab supervisor in 1985 despite his lack of a doctoral degree. His first success came with Geodon in the late 1980s. Another Pfizer chemist, John Lowe, had created a promising schizophrenia drug, but lab tests indicated it might be carcinogenic. After tinkering for a few weeks, Howard realized he could stabilize the molecule (and thus eliminate the toxicity problem) by adding a single chlorine atom. When he first made Geodon he threw it away because it looked like useless gray sludge. The next day he realized his mistake and dredged it out of the trash.
Howard has played a more central role in designing the quick-acting antidepressant. Prozac and the like work by boosting levels of serotonin, a transmitter of brain signals, whose levels are lower in depressed patients. But nerve cells have sensors called autoreceptors that detect this flood of new serotonin and try to counteract its effect. Only after several weeks of treatment, researchers believe, do the sensors become desensitized to the new elevated serotonin level, allowing a patient's mood to brighten.
Sprouse and others theorized in the early 1990s that drugs that blocked these self-defeating autoreceptors could create a faster impact by causing an immediate, long-lasting flow of serotonin that would lift a patient's mood in days. Howard was brought in to craft a chemical that zeroed in on and blocked the serotonin autoreceptors, while avoiding numerous other similar brain receptors required for healthy functioning. Screening Pfizer's compound collection produced some promising leads, but the compounds turned out to be toxic. The problem seemed to be a long spine that connected the two business ends of the molecule responsible for gumming up the autoreceptors. In a nifty piece of atomic surgery, Howard removed the skeleton and replaced it with a novel nontoxic structure, while retaining the two crucial good ends. The resultant boomerang-shaped molecule was able to surgically strike the bad serotonin autoreceptors and spare the good receptors.
Animal tests show that the compound does indeed hit the autoreceptors, and early human trials found no big safety problems. Now Howard must endure the long wait to find out whether his new compound works in humans. The trials are likely to be long and difficult: Because of the murky and variable nature of depression, it is difficult to measure antidepressant effectiveness at all, let alone subtle differences in the timing of effectiveness. Pfizer hopes to get an early readout by the fall from its second-stage trials involving hundreds of patients. Howard is trying not to get his hopes up too soon. Geodon was a decade-long roller-coaster ride, its approval repeatedly delayed because of safety concerns before it finally got the nod in 2001.
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URL: http://www.dr-bob.org/babble/20041211/msgs/430269.html