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First-time Disclosures of Clinical Candidates

Frailty, erectile dysfunction, scarring, and thrombosis/atherosclerosis drugs introduced

May 10, 2004 | A version of this story appeared in Volume 82, Issue 19

Balasubramanian (left) and Barrish organized this year's first-disclosures session.
Balasubramanian (left) and Barrish organized this year's first-disclosures session.

If information yearns to be free, it's likely to be somewhat disappointed when it first emerges at a drug company. But for the past four years, pharmaceutical researchers have had an opportunity to disclose their latest drug discovery achievements at an annual symposium held at American Chemical Society national meetings. The ground rules are that drug candidates must have entered a clinical development phase and that their structures be publicly revealed at the symposium for the first time.

The tradition continued last month in Anaheim at a Division of Medicinal Chemistry session on "First Time Disclosures." There, researchers from major pharmaceutical companies introduced new agents for frailty, erectile dysfunction, dermal scarring, thrombosis, and atherosclerosis.

"The identification of a clinical candidate is a significant milestone in the career of any medicinal chemist," said symposium co-organizer Balu N. Balasubramanian, director of discovery chemistry at Bristol-Myers Squibb (BMS), Princeton, N.J. "As such, the presentation of the candidate at the first-time disclosures symposium is an exciting opportunity to communicate this work to one's peers."

Joel C. Barrish, BMS vice president of immunology chemistry and chemical synthesis and the other co-organizer of this year's session, added that "extraordinary creativity and hard work go into the design of these molecules to optimize their activity against biological targets of interest as well as their in vivo properties, while avoiding the many potential off-target liabilities that can derail their development."

An example of that was a BMS team's discovery of a novel series of compounds that can potentially benefit patients with age-related functional decline. "An increasing number of people are at risk of becoming frail," said BMS Associate Director of Discovery Chemistry Lawrence G. Hamann. "Common everyday tasks--such as lifting a bag of groceries, getting out of a chair, or closing a door--can become incredibly difficult for people as they become frail. Perhaps by preventing or reversing muscle decline, you can allow such people to maintain independence longer."

In frail patients, low muscle strength is often associated with low blood levels of the male hormone testosterone. Testosterone is sometimes administered to men with symptoms of muscle wasting and age-related functional decline. However, the hormone can also have "hyperstimulatory" effects on the prostate, which can exacerbate preexisting prostate cancer and benign prostatic hyperplasia (noncancerous enlargement of the prostate).

IN ADDITION, Hamaan noted that testosterone cannot be given orally because it's rapidly metabolized. It therefore has to be administered as a patch or gel. Patches are optimally applied genitally, a form of administration that patients often dislike. And testosterone in gels can be transferred inadvertently to people who come in contact with the patient's skin.

A potential alternative to testosterone is the use of SARMs (selective androgen receptor modulators), compounds with activity similar to that of testosterone and other male hormones. SARMs are being investigated for treatment of hormone-related conditions in men--such as age-related functional decline, hypogonadism (hormone deficiency), benign prostatic hyperplasia, and andropause (ADAM, for "androgen decline in the aging male")--as well as conditions in both men and women, such as osteoporosis and sexual dysfunction. The corresponding treatments aimed at hormone-related conditions in women are SERMs (selective estrogen receptor modulators).

Hamann and coworkers at BMS have discovered a series of SARMs that are orally active and can potentially improve muscle strength and function with reduced risk of prostate hyperstimulatory effects. Studies in rodents of one of these agents, BMS-564929, showed that it is 230 times more potent than testosterone. In addition, it is 160-fold more selective for muscle-strengthening effects over prostate-stimulatory effects, compared with the twofold selectivity of testosterone. "So theoretically you can push the dose higher to see beneficial effects before you would begin to see any deleterious effects" such as prostate hyperstimulation, Hamann said. "This has the potential to really be a useful approach in an area of unmet need."

To find BMS-564929, BMS scientists did a computer analysis of known steroids and other small molecules that exhibit activity at androgen receptors and developed a four-point pharmacophore--a model of four structural and energetic drug features associated with the receptor interactions. They selected a library of 1,400 compounds from the BMS compound library that fit the model and screened them for activity.

"Out of that came some novel scaffolds, which we then elaborated with classical medicinal chemistry to arrive at the molecules we currently have," Hamann said. The best among these was BMS-564929, which is "currently in human clinical trials for indications of age-related functional decline in men," he said.

Chemists (from left) Andrew Stamford, Claire Lankin, Boyle, Samuel Chackalamannil, and Yuguang Wang helped cook up Schering-Plough's new erectile-dysfunction drug candidate, SCH 446132.
Chemists (from left) Andrew Stamford, Claire Lankin, Boyle, Samuel Chackalamannil, and Yuguang Wang helped cook up Schering-Plough's new erectile-dysfunction drug candidate, SCH 446132.

A Schering-Plough research team reported at the symposium on the discovery of SCH 446132, a phosphodiesterase type 5 (PDE5) inhibitor developed as a treatment for male erectile dysfunction (ED, sometimes called impotence). The three current commercial ED drugs--sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis)--all inhibit PDE5. PDE5 inhibitors can be used to treat ED because they increase levels of cyclic guanosine monophosphate (cGMP) in the nitric oxide pathway that leads to penile erection.

"We sought to develop a selective inhibitor of PDE5 that had greater selectivity over other PDE isozymes than current drugs, which could result in an oral ED treatment with a more desirable side-effect profile," said Craig D. Boyle, a principal scientist at Schering-Plough Research Institute, Kenilworth, N.J. The group's initial leads came from a previous PDE1/PDE5 dual inhibitor program for the treatment of hypertension [J. Med. Chem., 40, 2196 (1997)]. Boyle and coworkers modified two series of those compounds (cyclic guanines and xanthines) to improve their selectivity for PDE5 over two other PDE enzymes, PDE1 and PDE6.

They identified a potent inhibitor from the xanthine series that had good PDE5 selectivity over the other PDE isozymes and showed promising activity in a rabbit assay [Bioorg. Med. Chem. Lett., 12, 3149 (2002)]. But the agent had poor aqueous solubility. They converted a benzyl group to a m-bromo-p-methoxybenzyl moiety to optimize PDE5 potency and selectivity. They added a hydroxyethyl substituent to improve aqueous solubility. And they converted an amino group to an amino alcohol to enhance solubility.


THE RESULT was SCH 446132, a potent PDE5 inhibitor with excellent selectivity over all other PDE isozymes and good aqueous solubility. The drug's pharmacokinetics (absorption, distribution, and elimination properties) are similar to those of sildenafil--fast onset and moderate clearance--and the compound is active in an in vivo dog model of erectile dysfunction. "No significant preclinical toxicity was noted, and SCH 446132 is currently in human clinical trials," Boyle said.

At Pfizer Global Research & Development's Sandwich Laboratories, in England, a group led by Associate Director of Medicinal Chemistry Simon Bailey (now at Pfizer's La Jolla Laboratories, San Diego) discovered a new agent for treatment of dermal scarring. The drug, called UK-383,367, is a potent, selective, and structurally novel inhibitor of procollagen C-proteinase. This enzyme plays a key role in collagen processing, but no inhibitors for it were previously known.

"We had some market research that suggested that in the U.S. alone there are 6 million surgeries annually that have a risk of developing an unsightly scar--mainly on the face or chest," Bailey said. Besides detracting from appearance, the scars can also impair movement if they occur over joints.

The underlying process that leads to such scars is excessive, unregulated collagen deposition and accumulation at the site of an injury or burn. The deposition pathway involves procollagen C-proteinase-catalyzed cleavage of a soluble form of collagen to give an insoluble form that then assembles into fibrils.

Bailey and coworkers sought an inhibitor for the enzyme primarily as a way to interfere with scar formation. "Following wounding, we had evidence that this enzyme would be active at high levels for a period of days, if not weeks," Bailey said. "We also hypothesized that even with a scar that had existed for a while, treatment with these kinds of compounds might lead to an improvement in the overall scar appearance through attenuation of a remodeling process that goes on. But the short-term aim of the program was to find something that would act on scars during the initial formation period, which is typically days to weeks after an injury." The Pfizer team also believed that inhibiting the collagen deposition pathway might be useful for treating fibrosis (formation of excess fibrous connective tissue) in internal organs such as kidney, liver, and heart.


THE CHALLENGE was to design compounds that could be applied topically to closed wounds and that would penetrate the epidermis and enter the dermis, where collagen processing takes place. The compounds would have to be applied as sterile formulations so they would not cause irritation or interfere with normal wound management. And the researchers wanted the compounds to be cleared efficiently once they entered the systemic circulation. "There are lots of collagen remodeling processes that go on in the body normally, so we didn't want to inhibit the enzyme systemically," Bailey explained.

Because no procollagen C-proteinase inhibitors were known, the Pfizer team had to start from scratch. They first screened the Pfizer compound file for agents that had shown activity against matrix metalloproteases, which are structurally similar to procollagen C-proteinase. "What came out of that were a lot of peptidic active compounds and a few nonpeptidic actives," Bailey said.

The group's key breakthrough was to take structure-activity relationship (SAR) data they had obtained in the peptidic series and transfer the data to a nonpeptidic series. "One modification gave us a 200-fold jump in activity" from 6 mM down to about 35 nM, Bailey said. "At the same time, we were interested in having selectivity over other enzymes, and the same modification that gave us a rise in activity also essentially eliminated matrix metalloprotease activity. So with one modification we were able to go from weak, nonselective hits to pretty potent, very selective compounds."

Once Bailey and his coworkers were in the right potency region, he added, "we carried out some SAR studies, and we found a region of the molecule that was relatively insensitive to substitution, so we could make lots of changes there without affecting potency. We used that region to tune the physicochemistry properties to ensure good skin permeability and high systemic clearance." The result was UK-383,367, which is currently in clinical development.


Tiplaxtinin, a novel agent that fights thrombosis (blood vessel blockage), atherosclerosis (arterial deposits and constriction), and related conditions by controlling plasminogen activator inhibitor-1 (PAI-1), was discovered by principal research scientist Hassan Elokdah and colleagues at Wyeth Research, Princeton, N.J.

PAI-1 is a glycoprotein that inhibits two enzymes--tissue type plasminogen activator and urokinase type plasminogen activator. Patients with deep-vein thrombosis and myocardial infarction (heart attack caused by coronary blockage) often have high levels of PAI-1 in their blood, suggesting that the glycoprotein deters clot disintegration. Individuals lacking the PAI-1 gene seem to be healthy, indicating that a drug that lowers PAI-1 concentration would be safe.

PAI-1 exists in three different forms--active, latent, and cleaved. Only the first of these conformations inhibits the two enzymes, but it is unstable and converts spontaneously to the inactive latent form. "These attributes made active PAI-1 a challenging target to pursue through structure-based design," Elokdah said.

To identify an agent that would control active PAI-1, Elokdah and coworkers first carried out a high-throughput screen of the Wyeth compound library. Optimization of one of the hits from the screen led to a series of indoles that were potent and effective PAI-1 modulators. Subsequent refinement of the compounds' SAR properties yielded tiplaxtinin (PAI-039), which binds active PAI-1 with high affinity and exhibits good selectivity against binding of latent PAI-1. "This unique binding profile resulted in functional inactivation of PAI-1 in vitro," Elokdah said.

Tiplaxtinin was efficacious in rats with chemically induced carotid thrombosis, in dogs with electrolytically induced coronary thrombosis, and in mice with chronic atherosclerosis (arterial occlusion), suggesting that it has promise for treatment of such conditions.

In addition, the drug is orally active, highly bioavailable (available to the target tissue after administration), metabolically stable, well tolerated in animal models, and nongenotoxic. "Tiplaxtinin is a first-in-class agent that was advanced by Wyeth to human clinical trials," Elokdah said.


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