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CEPHALON
UNVEILING DRUG CANDIDATES
Pharmaceuticals, potentially clouding the future of Cephalon’s R&D projects (C&EN, April 4, page 16). Following Hudkins’ disclosure, John F. Kadow, director of virology discovery chemistry at Bristol-Myers Squibb in Wallingford, Conn., told the story of BMSACS MEETING NEWS: Medicinal chemists reveal potential drugs 663068, a potential treatment for the hufor HIV, Alzheimer’s, diabetes, and irritable bowel syndrome man immunodeficiency virus (HIV). CARMEN DRAHL, C&EN WASHINGTON Over the past 30 years, HIV has become a manageable disease for many patients. But some patients don’t respond to availTHE ANAHEIM Convention Center last nate lipophilicity entirely, because some able treatments. “A new drug with a new month hosted the latest installment of an lipophilicity is necessary for getting a drug mechanism of action might be useful in a American Chemical Society national meetinto the brain. different combination,” which might help ing tradition—the first public disclosure of By placing lipophilicity among its top patients who are resistant to established the structures of five experimental medipriorities, the team eventually drugs, Kadow said. cines. The event highlighted compounds developed irdabisant, a drug BMS targeted the earliest that had reached human clinical trials, as candidate taken in pill form stage of viral attachment: the COGNITION CREW The well as the chemistry strategies that led that acts as an inverse agonist Cephalon team that binding of the envelope prodiscovered CEP-26401 researchers to each molecule. at the histamine H3 receptor. tein gp120, a glycoprotein on includes (from left) Robert J. DeVita, a director of medicinal The molecule not only blocks the virus’s surface, to CD4, a Hudkins, Mark Ator, Rita chemistry at Merck’s Rahway, N.J., disthe receptor’s response to glycoprotein on the surface Raddatz, Lisa Aimone, covery chemistry site, presided over the histamine but also blocks the of T cells. The envelope proMehran Yazdanian and, session, held in the Division of Medicinal receptor’s low-level baseline tein’s Achilles’ heel is a highly John Mallamo. Chemistry and entitled “First Time Disclosure of Clinical Candidates.” The symposium was organized by Albert J. Robichaud, vice president of chemistry at Danish drugmaker H. Lundbeck, and was sponsored by Gilead Sciences. Starting off the symposium, Robert L. Hudkins, distinguished scientist at Cephalon in Frazer, Pa., disclosed the structure of CEP-26401 (irdabisant), a histamine H3 receptor blocker for treating cognitive deficits in multiple diseases, including Alzheimer’s disease. The histamine H3 receptor regulates the release of multiple neurotransmitters that play a role in memory, attention, and cognition. Blocking the H3 receptor would promote release of those activity, Hudkins conserved small pockH neurotransmitters, in effect aiding several explained. et where CD4 binds. O N N cognition-related processes with one pill, In rats, irdabisant BMS’s small-molecule Hudkins explained. improved short-term drug candidates were The Cephalon team’s quest drew on the memory, something found to bind in that history of failures in the H3 area. “Some that is thought to small pocket, Kadow O N compounds from the industry have moved be impaired in Alsaid. CEP-26401 (Irdabisant) into clinical trials, but many have failed,” zheimer’s disease. BMS-663068 is the Hudkins said. No drug targeting this histaPhase I clinical trials latest in a series of HIV mine receptor has yet reached the market, for irdabisant, which evaluate safety and attachment blockers that the company has he added. Several of the issues that led to dosing, will finish this month, and Cephabrought to human clinical trials. Kadow earlier failures, such as cardiovascular side lon plans to advance irdabisant to Phase II and his colleagues optimized the screening effects, could be tied to the molecules’ trials. Cephalon is currently the object of hit BMS-216 to obtain BMS-378806. But lipophilicity. Yet Cephalon couldn’t elimia hostile takeover bid by Canada’s Valeant when the compound was tested in humans,
SCIENCE & TECHNOLOGY
W HE RE A R E T H EY NOW ?
Revisiting Disclosures From Years Past C&EN has covered the “First Disclosures” symposium each year for nearly 10 years. This new feature returns to previously disclosed compounds to see how they are faring. MLN518 (now tandutinib) The road from clinical trials to Food & Drug Administration approval O can be long. For N MLN518, an N N N N anticancer drug H candidate from Millennium PharmaceuO OCH3 ( )3 ticals (today, N Millennium: The Takeda Tandutinib Oncology Co.) that had its structure disclosed at the spring 2002 ACS national meeting, the journey is roughly a decade old. The molecule has not yet been FDA approved. MLN518 blocks a kinase enzyme called FLT-3, part of a family of cell-signaling enzymes that has been implicated in a variety of cancers (C&EN, May 13, 2002, page 35). In 2002, the company had initiated Phase I clinical trials of MLN518, which was later renamed tandutinib. The trials involved patients with acute myelogenous leukemia (AML), a form of cancer marked by rapid accumulation of abnormal white blood cells in blood and bone marrow, and a form where more than a quarter of patients have mutations in FLT-3. In 2006, the company published the results of that trial (Blood, DOI: 10.1182/blood-2006-02-005702). The trial was too small to test tandutinib’s
not enough of it reached the bloodstream to work against HIV. The team’s next effort, BMS-488043, lowered some patients’ HIV levels in clinical trials but had to be taken with high-fat meals because of low solubility. BMS-663068 IS a phosphate prodrug
that arose from the team’s efforts to boost BMS-488043’s solubility and antiviral activity while maintaining its safety. The prodrug improved solubility, while replac-
antileukemia activity, and some patients experienced side effects such as muscle weakness. However, two patients with FLT-3 mutations exhibited evidence of an antileukemia effect. So Millennium continued to study the drug in multiple clinical trials to confirm that effect. One of those trials, a Phase I/II clinical trial involving AML patients, combined tandutinib with two other chemotherapeutics, O cytarabine and daunorubicin. In that trial, 21 of 29 leukemia patients on the combination treatment achieved complete remission (IDrugs 2008, 11, 46). In another of the trials, a small Phase II study of tandutinib in patients with metastatic kidney cancer, side effects such as fatigue emerged in 30% of the patients on the drug (Invest. New Drugs, DOI: 10.1007/s10637-0109516-1). Clinical trials of tandutinib are ongoing involving patients with F solid tumors such as glioblastomas, according to the ClinicalTrials.gov registry. Millennium did not respond to requests for comment on N the drug’s status.
merged with Merck in November 2009. Vorapaxar was inspired by himbacine, a molecule found in the bark of Australian magnolia trees (C&EN, April 18, 2005, page 40). It selectively blocks a protein called protease-activated receptor 1 (PAR1), which is found on the surface of blood platelets. PAR-1 is activated by thrombin, a protease enzyme that has two big roles: helping platelets clump together and forming fibrin, the meshlike protein that’s a major component of blood clots. It was thought that by blocking PAR-1, vorapaxar would block platelet aggregation without interfering with clotting, thus reducing risk of heart attack without raising the risk of excessive bleeding. By this year, vorapaxar was being tested in tens of thousands of patients in multiple Phase III clinical trials. On Jan. 13, an independent data safety monitoring board made changes to two large vorapaxar trials. In one study, patients who’d had a prior stroke were taken off vorapaxar, and the second study was discontinued. On Jan. 19, Merck confirmed that for patients with a history of stroke, vorapaxar increased the risk of bleeding in the brain. This development was a blow to the thinking about the benefits H SCH-530348 (now of vorapaxar’s mechanism. H vorapaxar) However, the safety monitoring O O Since C&EN covered board recommended that N O the first disclosure of vorapaxar still be tested H H O H the blood-clot-preventing in more than 20,000 paVorapaxar drug candidate SCH-530348 in tients who do not have a history spring 2005, the molecule has of stroke, and Merck is committed been given the name vorapaxar. Origito doing so, said Brigham & Women’s nally discovered at Schering-Plough, Hospital cardiologist Eugene Braunwald, the drug candidate became part of chair of one large vorapaxar clinical study, in a Jan. 19 Merck press release. the Merck pipeline when Schering
ing a methoxy group with a heterocycle improved activity. In Phase IIa studies—a small-scale test of efficacy in HIV patients—BMS-663068 lowered viral RNA levels and increased counts of immune cells after eight days of treatment. A Phase IIb study, a larger efficacy test, is planned to start later this year, Kadow said. After Kadow, Emma R. Parmee, executive director and head of discovery chemistry at Merck in West Point, Pa., disclosed WWW.CEN-ONLINE.ORG
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the structure of MK-0893, which blocks the receptor for the hormone glucagon. The molecule is a potential treatment for type 2 diabetes. When glucagon activates its receptor, it triggers glucose production in the liver, thus raising glucose levels. Type 2 diabetics “produce more glucagon than they should, both before and after meals,” Parmee said. As a result, these patients produce too much glucose, and their glucose production levels directly correlate
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BRISTO L-MY ERS SQU IBB
duced in the gastrointestinal system,” Main told C&EN. Serotonin affects the GI tract in several ways, and studies relate high serotonin levels in the gut to GI disorders such as irritable bowel syndrome, which is marked by either diarrhea or constipation accompanied by abdominal pain. Lexicon typically chooses targets after in-depth analysis of knockout mice from its library, which contains knockouts of more than 5,000 different enzymes or receptors. This study was no exception. The team noticed that a mouse lacking tryptophan hydroxylase, a key enzyme for serotonin biosynthesis, had reduced serotonin levels
HIV GROUP The Bristol-Myers Squibb team
that developed BMS-663068 includes (front row, from left) Hua Fang, Zhongxing Zhang, Zhong Yang, Stephen Adams, Tao Wang, (middle row, from left) Juliang Zhu, Nannan Zhou, Betsy Eggers, Beata Nowicka-Sans, Zhiwei Yin, Dennis M. Grasela (back row, from left) Daniel Smith, Brian McAuliffe, Kap-Sun Yeung, Kadow, Timothy P. Connolly, John Bender, Alicia Regueiro-Ren, and Nicholas A. Meanwell.
added a methyl group at the benzylic position of their molecules. This strategy had not panned out with previous compound series, but the team attempted it anyway, a move that ultimately led them to MK-0893. “Don’t be afraid to try things you’ve tried before,” Parmee advised. “I was surprised how well it worked.”
A Leading FluoroMedChem Company in China
with the severity of their diabetes, Parmee said. “We looked at a lot of different chemical scaffolds” to find a glucagon receptor blocker that could be taken in pill form, Parmee said. The scaffolds Parmee discussed in Anaheim, Calif., were pyrazoles—which evolved from a urea—and benzimidazoles. Although the pyrazoles failed to block the glucagon receptor as well as the benzimidazoles did, the Merck chemists prioritized pyrazoles because they had fewer metabolic drawbacks. To improve the pyrazoles’ ability to block the receptor, they
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IN ANIMAL TESTS, MK-0893 was effica-
cious at lowering glucose production in the liver and had a favorable safety profile. According to the federal clinical trial registry ClinicalTrials.gov, several Phase II trials of the drug candidate in type 2 diabetics have been completed. MK-0893 does not appear in Merck’s Phase II pipeline in its most recent annual report. Also at the Anaheim session, Alan J. Main, executive vice president of pharmaceutical research at Lexicon Pharmaceuticals in Princeton, N.J., described LX1031, an orally administered serotonin synthesis inhibitor for treating irritable bowel syndrome. “People associate serotonin with the brain but the vast majority of it is pro-
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Shanghai AQBioPharma Co., Ltd www.aqbiopharma.com.cn
[email protected] FAX: 86-21-51370935X8011
M ERCK & CO.
SCIENCE & TECHNOLOGY
PICKING PRIORITIES Merck looked at several chemical scaffolds, including pyrazoles and benzimidazoles, in its search for a diabetes drug candidate. MK-0893 emerged from the pyrazoles. CH3 N F3C
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LEXICON PHARMACEUTICALS
in the gut but not in the and binding pockets, DIABETES TEAM The people behind Merck’s MK-0893 include the team opted to debrain. From this data (from left) Yusheng Xiong, John they went on to discover velop a serotonin synStelmach, Rui Liang, Parmee, that two subtypes of the thesis inhibitor that Chris Sinz, Ron Kim, Subha enzyme exist, one in the Raghavan, Linda Brockunier, and stayed out of the brain Dong-Ming Shen. gut and one in the brain, and remained in the implying that chemists GI tract, Main said. might be able to target the Two strategies that subtype in the gut to treat irritable bowel served the team well were making syndrome. molecules with molecular weights Because X-ray crystal structures reslightly above 550 and using highly povealed that the two subtypes of tryptolar functional groups such as an amino phan hydroxylase had similar active sites acid moiety to keep the compound from crossing into the brain. Both those strategies are evident in LX1031’s structure, he said. To confirm that LX1031 stays out of the brain, the team has performed animal studies with radiolabeled versions of the molecule. Neurological side effects have
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not been seen in clinical studies, Main said. LX1031 has completed Phase IIa clinical trials, which are an initial proof-of-concept test of efficacy, involving patients with nonconstipating irritable bowel syndrome, and the company plans to start larger Phase IIb cliniSEROTONIN SQUAD Lexicon chemists cal studies, Main said. behind LX1031 are (from left) Raj In the session’s final Devasagayaraj, Mark Bednarz, Matthew disclosure, South San Zhao, Peter Zhang, Main, Giovanni Francisco-based Elan Cianchetta, Ngiap-Kie Lim, and Brett Marinelli. Not pictured: Zhi-Cai Shi. Pharmaceuticals principal
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Lexicon optimized its highthroughput screening hit to keep it out of the brain and stay in the gastrointestinal tract, resulting in irritable bowel syndrome drug candidate LX1031.
closing their γ-secretase inhibitor BMS-708163 (C&EN, April 27, 2009, page 31). During the discovery process, the Elan team switched from molecules with a caprolactam scaffold to molecules with a pyrazole scaffold. Pyrazoles had both better avoidance of Notch and improved penetration into the central nervous system. The team also added a trifluoromethyl group and a cyclopropyl group to enhance their molecules’ metabolic stability. These strategies eventually led the chemists to ELND006.
CROSSING OVER Elan learned that its caprolactam drug candidates for Alzheimer’s disease lacked selectivity and brain penetration. A switch to pyrazoles improved both characteristics and led to ELND006. Br
O O
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IN HUMANS, the molecule didn’t interfere with Notch and lowered amyloid-β levels by up to 50%, as measured from cerebrospinal fluid. But ELND006 had N NH side effects in the liver that were unrelated to Notch, ELND006 Probst said. Elan’s development program for ELND006 was halted in October 2010. But because the adverse effects appear to be unrelated to the molecule’s mechanism of action, Elan is continuing to study other γ-secretase inhibitors at earlier stages of its pipeline, with the goal of finding a drug candidate that can put the question of amyloid-β to the test. Asked about the significance of the symposium, presider DeVita said that chemists attend the event largely for two reasons: “People want to see who’s innovating from a scientific standpoint, and people want to see what their competitors are working on.” But at the end of the day, “this symposium is about medicinal chemists’ creativity and problem-solving ability,” he added. ■ ELAN PHARMACEUTICALS
Elan’s caprolactam
CF3
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NEW Products Chemicals, Inc. An Employee-Owned Company Serving Customers Globally
Established 1964
CF3 OMe
N
scientist Gary G. Probst revealed the structure of ELND006, a molecule designed to treat Alzheimer’s disease by acting on the enzyme γ-secretase. Elan is one of many companies eager to test whether halting production of amyloid-β, the peptide behind the plaques marring Alzheimer’s patients’ brains, can slow or stop the progression of the disease (C&EN, April 5, 2010, page 12). And γ-secretase is one of two key enzymes in amyloid-β production, Probst explained. Selectivity was the name of the game in Elan’s medicinal chemistry program, Probst said. γ-Secretase is a membrane-bound protease that cleaves several peptide substrates besides amyloid-β, including the critical transcription factor Notch, which is involved in events such as cell-to-cell communication. “You want your inhibitor to tell γ-secretase to stop producing amyloid-β peptides but to continue to produce Notch,” Probst said. At the spring 2009 ACS national meeting in Salt Lake City, chemists at Bristol-Myers Squibb also emphasized the importance of this selectivity when disGAMMA GROUP Elan’s
WWW.CEN-ONLINE.ORG
P
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team behind ELND006 includes (from left) Ying-zi Xu, Ted Yednock, Danielle Aubele, Erich Goldbach, Beth Brigham, Mike Dappen, Al Garofalo, Dan Ness, Michael Ye, JohnMichael Sauer, Roy Hom, Hing Sham, Anh Truong, Probst, Guriq Basi, Simeon Bowers, and Kevin Quinn.
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15-1157
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44-7783
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