By Randall Osborne

West Coast Editor

Five months after Synaptic Pharmaceutical Corp. learned that Merck & Co. was quitting development of the partnership¿s lead compound for benign prostate enlargement, Merck cut off the flow of money altogether and relinquished its license to Synaptic¿s alpha-adrenergic technology.

¿I think it¿s good news,¿ said Kathleen Mullinix, president and CEO of Synaptic, of Paramus, N.J. ¿I¿m thrilled.¿

The technology validated a target, proving that the drug works without cardiovascular side effects, and now may be taken further by another partner.

News of the deal¿s end didn¿t hurt Synaptic¿s stock (NASDAQ:SNAP), which closed Thursday at $12.875, up 12.5 cents.

Synaptic¿s relationship with Whitehouse, N.J.-based Merck began in 1993, when they teamed up in what was described as a potential $20 million deal to work on a series of compounds that may be useful in treating urinary retention problems associated with enlargement of the prostate gland. Alpha adrenergic neuroreceptor blockers had been shown to cause the smooth muscles of the prostate to relax, relieving the pressure that an enlarged prostate places on the urethra. (See BioWorld Today, Dec. 20, 1993, p. 1.)

In 1996, Merck extended the deal for another year. But, last fall, the lead drug for benign prostatic hyperplasia faltered in Phase IIa clinical trials. The study, involving a selective alpha-1a antagonist, showed Synaptic¿s alpha-1a adrenergic receptor was a valid target, but it demonstrated limited oral bioavailability and showed it had potential for drug interactions. Merck discontinued the compound, and Synaptic said its collaborator was looking for a replacement lead drug. (See BioWorld Today, Oct. 30, 1996, p. 1; and Sept. 14, 1999, p. 1.)

¿The compound fell out of bed for reasons that had nothing to do with the mechanism, and [Merck] worked enormously hard to get a backup,¿ Mullinix told BioWorld Today. Experiments with a second drug candidate also showed ¿some hint there might be a toxicity problem,¿ she said. The drug altered liver enzymes in a dog.

Meanwhile, she said, other companies sought licensing from Synaptic, but were prevented by the Merck deal. Those options can be pursued now.

¿One [question in drug development] is: Do you have a target that mediates the effect you hope it mediates?¿ Mullinix said. ¿That¿s what our technology does. But nobody on the planet that I know of can look at an individual compound and tell you, a priori, whether it¿s going to affect liver enzymes, break chromosomes or be absorbed.¿

Mullinix would not disclose how much Synaptic made from the Merck deal before it ended.

Alpha-adrenergic receptors, activated by the neurotransmitter noradrenaline, play key roles in regulating involuntary physiological functions, such as blood pressure, heart rate and smooth muscle tone. The family of alpha-1 and alpha-2 receptors contains at least six subtypes, and Synaptic said it discovered the genes that code for the human alpha-1a, alpha-1b, alpha-1d and alpha-2b receptors.

Synaptic, founded in 1987, uses what it calls ¿human receptor-targeted drug design technology¿ to find and clone genes that code for human receptors. With licensees, it¿s aiming to define the function of such receptors, and the disorders to which they may be connected.

¿We have a very large patent estate on a variety of receptors we¿ve discovered, and it¿s continuing to grow,¿ Mullinix said.

In January, Synaptic signed a three-year research and licensing agreement with Tokyo-based Kissei Pharmaceutical Co. Ltd. to identify and develop drugs capable of acting through novel receptors. Terms were not disclosed. (See BioWorld Today, Jan. 26, 2000, p. 1.)

Synaptic also has preclinical programs targeting pain with Grunenthal GmbH, of Aachen, Germany; a preclinical program for obesity with Novartis AG, of Basel, Switzerland; and preclinical studies for depression, migraine and obesity with Eli Lilly & Co., of Indianapolis, as well as a Phase I trial with Lilly for serotonin drugs to treat depression. Lilly last year dropped development of a lead candidate in migraine before a Phase III trial, after looking at animal toxicology data. (See BioWorld Today, March 22, 1999, p. 1.)

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