Adventures in Medicinal Chemistry

Adventures in Medicinal Chemistry

CHAPTER TWO Adventures in Medicinal Chemistry: A Career in Drug Discovery William J. Greenlee MedChem Discovery Consulting, LLC, Teaneck, New Jersey,...

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CHAPTER TWO

Adventures in Medicinal Chemistry: A Career in Drug Discovery William J. Greenlee MedChem Discovery Consulting, LLC, Teaneck, New Jersey, USA

Contents Acknowledgments References

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I was born into a family of chemists. My father, uncle, and grandfather were all chemists. As a result, my brother Mark and I were exposed to laboratories and the basic concepts of chemistry from an early age. We got used to having our father enliven family outings by throwing a lump of sodium into the nearest body of water and having complex chemistry discussions with our grandfather. I got my own start in the laboratory during high school, synthesizing acetylenes using reactions in liquid ammonia, running Grignard reactions, and monitoring large-scale distillations for my father’s new catalog company “Chemical Samples Company.” During that time, my intention was to study medicine, but I was drawn into the world of organic chemistry around me. I went on to major in chemistry at Ohio State University, doing undergraduate research with Paul Gassman. I completed my Ph.D. with Robert B. Woodward at Harvard University, and after postdoctoral work with Gilbert Stork at Columbia University, I joined Merck Research Laboratories in Rahway, New Jersey in 1977. It was not a surprise that Mark also got his Ph.D. in chemistry and has had a long and successful career as a medicinal chemist. One thing that drew me to organic and (especially) medicinal chemistry was the concept of creating a new chemical compound that had never existed before. The idea that I could do that, and that the compound might be useful in treating disease was a powerful motivation. Later, when I was working at the bench, one of my favorite occurrences was spotting the first Annual Reports in Medicinal Chemistry, Volume 49 ISSN 0065-7743 http://dx.doi.org/10.1016/B978-0-12-800167-7.00002-X

#

2014 Elsevier Inc. All rights reserved.

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crystals growing in a solution of a new compound. Creating a new compound and watching how it forms crystals for the first time was a nearreligious experience for me. Although I have been out of the laboratory for many years, I still dream about being back there doing experiments and experiencing the excitement of drug discovery. I began my career at Merck in the New Lead Discovery group led by Art Patchett, who had also received his Ph.D. at Harvard University with R.B. Woodward. The goal of my first project at Merck was to synthesize halovinyl amino acids as irreversible inhibitors for DOPA decarboxylase (for Parkinson’s disease (PD)) and alanine racemase (as potential antibacterial agents).1 This type of inhibitor was referred to as a “suicide substrate,” one that became reactive only after turnover by the enzyme target (also referred to as a “mechanism-based enzyme inactivator”). I was also able to work out a more general synthesis of β,γ-unsaturated amino acids using the Strecker reaction.2 Drugs with an irreversible mode of action fell out of favor for many years, but irreversible inhibitors of protein kinases have become popular, and there are now many examples of marketed drugs that form covalent bonds with the target protein. H X H2N

H CO2H

X = -F Fluorovinylglycine X = -Cl Chlorovinylglycine

By the time I arrived at Merck from Columbia, Art had already started a program to identify inhibitors of angiotensin-converting enzyme (ACE), to follow up on earlier discoveries made at Squibb (now Bristol-Myers Squibb). At the time, the antihypertensive drug Aldomet™ was a successful product for Merck, but would be off patent in a few years, and a drug that would treat hypertension with fewer side effects was a major goal. I was asked to join the effort and was privileged to be part of the team, along with Matt Wyvratt, Eugene Thorsett, and others, who discovered enalapril and lisinopril, both of which became important drugs for Merck.3 For many of us, this was our first experience working with amino acids and small peptides, and doing reactions and workups in aqueous solution. The ACE inhibitor program was successful even though the X-ray crystal structure of ACE was not available. Amazingly, the details of the structure and the fact that ACE has two nonidentical active sites were not known until many years later.

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After ACE inhibitors were moving ahead in development, Merck and other companies shifted their attention to renin inhibitors, which block an earlier step in the renin–angiotensin pathway, and were thought to have potential advantages. Merck had started working on renin even before the ACE inhibitor program began, but the initial screen using porcine renin had not yielded viable hits. Like most other companies, Merck pursued a peptidomimetic approach to renin inhibitors, and the team at the Merck West Point site, led by Dan Veber and Joshua Boger, used the X-ray crystal structure of a fungal aspartic protease (Rhizopus pepsin) as a model enzyme. NH2 EtO

O N H

HO

CH3 N O

Enalapril (Vasotecä)

O

OH

O N H

N O

O

OH

Lisinopril (Prinivilä)

Their elegant work led to a potent and selective hexapeptide inhibitor, but oral bioavailability was low, and the program was eventually put on hold. A few years later, we began a new effort in Rahway, now guided by a published X-ray structure of human renin. We made significant progress in reducing the peptide nature of our inhibitors and identifying potent macrocyclic inhibitors,4 but we could not achieve the desired profile for an orally bioavailable inhibitor. At one point, there were over 20 companies with renin inhibitor programs, but none of the resulting candidates progressed beyond early clinical trials. It became clear that identifying peptidomimetics with drug-like properties would be a difficult challenge. It was over 20 years later (2007) when the first renin inhibitor, aliskiren, was approved for treatment of hypertension.5 It was therefore very exciting when DuPont Pharmaceuticals disclosed the first potent nonpeptide angiotensin II receptor antagonist and reported that it had efficacy in a rat model of hypertension. Rather than inhibiting the formation of angiotensin II, the receptor antagonist losartan blocks the action of the peptide at its receptor. With encouragement from senior management, the Merck renin inhibitor program was immediately abandoned, and all effort shifted to the new target. I soon found myself leading a large medicinal chemistry effort with an ambitious goal to identify a development candidate without delay. However, after a few months, Merck announced a

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new collaboration with DuPont Pharmaceuticals to develop their candidate losartan (Cozaar™). Our medicinal chemistry program and the ongoing program at DuPont Pharmaceuticals led by Ruth Wexler were merged into a combined effort to identify backup and second-generation antagonists. This work led to several backup candidates, including 1, MK-996, and DuP532 that were derived from the losartan chemotype.6,7 It had become clear that there are two receptors for angiotensin II, AT1 and AT2, and that losartan blocks only AT1 receptors. A potent AT2 antagonist had been disclosed by a group at Parke-Davis, but despite numerous studies, the signaling pathways and roles of this receptor were unclear (and still are). By modifying MK-996 and losartan, the team was able to identify potent dual AT1/AT2 antagonists such as 2 and XR510, but in the absence of a clear understanding of the AT2 receptor, none of these were taken forward into development.8 In the meantime, Cozaar™ was launched as a monotherapy and in combination with hydrochlorothiazide (Hyzaar™), and both were very successful drugs for treatment of hypertension. Several other AT1 antagonists (also called angiotensin receptor blockers) based on the losartan lead were launched by competitors and also became successful drugs (valsartan, candesartan, telmisartan, irbesartan, eprosartan, azilsartan, olmesartan). OH

N N N N

N

Cl

H3C

N N N N

N

H

N N

nBu

H3C

N

Et

Losartan (Cozaarä) H3C N H3C

N

1 O

H O N O S

N

Ph Ph

N

N

H3C

N

O

iPn

O

nBu

O

2

nPr

O

H3C

N (3-Pyr) F

O N N

H O N S

Et

MK-996

Et

O

N

H

O

Et

H

nPr XR510

N H O N O S

O

N O

iPn

H3C

N

H O N S O

Et

S

3

iBu

O

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One day during our backup program, Pete Siegl, who directed the Merck pharmacology effort at West Point, called to tell me that one of our “antagonists” had raised blood pressure when dosed to rats. In fact, we had discovered the first nonpeptide AT1 agonist, 3.9 This compound was found to be a full agonist of the AT1 receptor, with a much longer duration of action than angiotensin II, which is rapidly degraded. Although nonpeptide agonists of peptide G-protein-coupled receptors are now common, at that time 3 was the only such compound identified outside of the opioid receptor field. We were astounded by how small a modification in structure was required to shift an antagonist to an agonist.10 Recently, 3 became the starting point for design of AT2 selective agonists (without effects on blood pressure) that are being explored for potential utilities.11 Soon after we completed our angiotensin II program, the discovery of the vasoactive peptide endothelin was reported, and it was demonstrated to be the most potent vasoconstricting peptide to date. There was hope that blocking the endothelin receptors ETA and ETB, or preventing biosynthesis of endothelin by blocking endothelin-converting enzyme, would provide a novel (and possibly superior) approach to treating hypertension. Working from screening leads, we were able to identify potent dual ETA/ETB receptor antagonists, including 4.12 A few of our antagonists also had activity as angiotensin receptor antagonists, and remarkably we discovered compounds that blocked all four receptors (ETA, ETB, AT1, AT2) with nanomolar affinity.13 While this work did not continue at Merck, others followed up on similar leads and were able to demonstrate reduction of blood pressure in hypertensive patients.14 A number of selective endothelin receptor antagonists have been developed by others, but (similar to the situation with the angiotensin II receptors) the ETA receptor appears to be linked to vasoconstriction, while the roles of the ETB receptor are still unclear. Interestingly, both ETA selective (ambrisentan) and dual ETA/ETB antagonists (bosentan, macitentan) are approved for treatment of pulmonary arterial hypertension. O

OH

O O O

N H O O 4

O S

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Art Patchett’s interests in medicinal chemistry were very broad, and working with him provided me and others with broad training in medicinal chemistry. I also benefitted greatly from working with other managers and mentors at Merck, including Burt Christensen, Ralph Hirschmann, and Tom Salzmann. Although I was mostly involved in cardiovascular programs, I also had the opportunity to work on medicinal chemistry programs to discover antibacterial and antifungal agents and several projects in inflammation. Merck was an outstanding place to work, and I was privileged to be there during the “most admired” era of a world-class company. After nearly two decades at Merck, I accepted a position at ScheringPlough in Kenilworth, NJ, to lead the Cardiovascular and CNS Medicinal Chemistry group. I was excited to join the Schering-Plough team and to work directly with Catherine Strader, who had also recently relocated from Merck. I had been fascinated by neuroscience for many years, and the opportunity to contribute in this area was particularly attractive. I quickly found myself involved in programs for Alzheimer’s disease (muscarinic M2 receptor antagonists), PD (adenosine A2A antagonists), and schizophrenia (dopamine D4 antagonists). Many of our CV/metabolic diseases projects (e.g., NPY5 antagonists, MCHR1 antagonists, MC4 agonists) also involved targets residing in the CNS, so most of the programs we took on required drug candidates with good brain penetration. This was a steep learning curve for me, since designing drugs for CNS penetration adds a new dimension of complexity to lead optimization. I was also gaining an appreciation for the liabilities of CNS side effects in otherwise excellent drug candidates. One of our most challenging CNS programs was to identify a potent and selective adenosine A2A receptor antagonist for the treatment of PD. This project was initiated and actively promoted by Ennio Ongini at Schering-Plough’s Neuroscience Center in Milan, Italy. Ennio and his group had produced a very convincing set of data in rodent models of PD for the potent A2A antagonist SCH 58261, which had been designed and synthesized by his collaborator Professor Pier Baraldi at the nearby University of Ferrara.15 This antagonist, which was only modestly selective versus the A1 receptor (10-fold), had extremely low aqueous solubility and had to be dosed in DMSO by intraperitoneal injection.

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NH2 N

N N N

N N

O

SCH 58261 NH2 N H3C O

O

N

N N N

N N N

O

Preladenant

Although improving selectivity was straightforward, increasing solubility while maintaining robust activity in the in vivo models turned out to be a major challenge. Many attempts to reduce the complexity of the tricyclic core and replace the furan ring gave antagonists with high binding potency (1–5 nM), but led to loss of activity in the primary rat catalepsy model, despite high free drug levels in the brain. The adenosine antagonist program was not unique in this respect, and similar experiences in more recent programs have convinced me that we do not yet fully understand how to design effective CNS drugs. The CNS multiparameter optimization approach introduced recently by Pfizer16 may be a step in the right direction. Of several thousand antagonists synthesized for the program, preladenant emerged as our development candidate, and it possessed the properties we believed to be essential for success.17 Preladenant demonstrated robust activity in rodent and primate models of PD and had excellent pharmacokinetics and receptor occupancy in humans. Unfortunately, although it showed promising activity in Phase 2 studies in PD, preladenant did not demonstrate sufficient efficacy in Phase 3 studies to support continued development. One of the first projects initiated soon after I joined Schering-Plough was a program to identify a potent thrombin receptor antagonist as a potential antiplatelet agent. Activation of the thrombin receptor, also known as protease-activated receptor-1 (PAR-1), activates platelets and promotes their aggregation as part of thrombus formation. Unlike most G-proteincoupled receptors that are activated by an external ligand, PAR-1 receptors are cleaved at their amino terminus by the enzyme thrombin, creating a new peptide sequence that functions as a “tethered ligand” to activate the

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receptor. We were extremely fortunate that one of the hits to emerge from high-throughput screening became an excellent lead for the program. The hit was an analog of the natural product Himbacine, which had been synthesized for another program at Schering-Plough. The chemistry team, headed by Sam Chackalamannil, brought two development candidates forward, but each of these ran into a toxicity issue. Fortunately, the team was able to address these issues, and the third candidate, SCH 530348 (vorapaxar), moved into clinical trials for prevention of arterial thrombosis.18 I was excited to have the opportunity to co-chair the Early Development Team for vorapaxar with Madhu Chintala, Head of Pharmacology for the preclinical program. After completion of the Phase 3 clinical program for vorapaxar (which enrolled over 41,000 patients), the NDA was filed in 201319 and was approved by the FDA in May of 2014. Vorapaxar (proposed trade name Zontivity™) is hoped to provide benefits in secondary prevention of heart attack and stroke.20 O

H H

O H3C

H N

H

H

O O

H

N

F Vorapaxar (Zontivityä)

Soon after the discovery of beta-amyloid-converting enzyme-1 (BACE-1) in 1999, Schering-Plough initiated a program to discover inhibitors of this enzyme which plays a key role in the biosynthesis pathway of beta-amyloid and formation of the extracellular plaques found in Alzheimer’s disease. I was highly motivated to be a part of this effort, since Alzheimer’s disease has affected my family, and I had seen the effects of this terrible disease. BACE-1 is an exceedingly challenging target, due to its location in organelles inside neurons in the brain. BACE-1 is anchored in the membrane, but its active site faces an aqueous environment that requires inhibitors with substantial aqueous solubility. At Schering-Plough, we screened our entire sample collection and drew upon external screening

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resources, but were unable to generate leads for our program. Efforts to work from nonpeptide renin inhibitors in the scientific and patent literature were also unsuccessful. Reluctantly, we began an effort to design a peptidomimetic BACE-1 inhibitor based on the amyloid precursor protein substrate. Although we were able to identify potent inhibitors with oral bioavailability using this approach, these inhibitors were P-glycoprotein (PGP) efflux substrates and showed exceedingly low brain penetration.21 Given these setbacks, it was very exciting when Dan Wyss and Yu-Sen Wang in our structural chemistry group presented us with fragment hits that they had identified using HSQC NMR screening. Follow up by X-ray crystallography provided several confirmed hits, including an isothiourea that bound in the BACE-1 active site, making multiple interactions with the two active site aspartic acids. The isothiourea was clearly an undesirable group to have in a drug molecule, and a key insight provided by Zhaoning ( Johnny) Zhu was to replace this basic group with a fivemembered heterocycle (iminohydantoin) in order to make similar interactions. A large team, led by Andy Stamford, worked to optimize the weak iminohydantoin lead, which later evolved into a six-membered ring series of iminopyrimidinones.22,23 The BACE-1 program was supported by chemists at Pharmacopeia, and later by chemists at Albany Molecular Research Inc. As with most CNS programs, achieving potent binding affinity was only part of the challenge. Although most potent inhibitors in the series reduced betaamyloid levels in plasma, reducing them in cerebrospinal fluid (CSF) and (especially) in cortex was much more difficult. We expected that a balance of lipophilicity, aqueous solubility, and low PGP efflux would be essential for good activity in the CNS. However, it also became clear that a high degree of inhibition of BACE-1 was required for CNS activity. Our failure to achieve good inhibition of BACE-1 in the cortex became a big concern, and it was fortunate that we identified an iminopyrimidinone (5) that showed good activity in both CSF and cortex with an ED50 of 6 mg/kg (po) in rats.24 SCH 900931, later renamed MK-8931, was shown to reduce A-beta-40 levels by over 80% in a Phase 1 rising multiple dose study.25 This inhibitor is now in Phase 3 clinical studies in Alzheimer’s disease patients. Throughout the BACE-1 program, the medicinal chemistry team received strong support from our structural chemistry group led by Corey Strickland, and from other groups in discovery research. Merck has made a strong commitment to develop MK-8931 in both mild-to-moderate AD and in patients with mild cognitive impairment.26 If successful, this inhibitor could make a major contribution to the treatment (and possibly prevention) of this terrible disease.

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H

N

S

H N H

H3C

NH

H HN S H

N

O

N

CH3 O

Cl

Cl 5

Fragment lead

After having succeeded in identifying a potent BACE inhibitor for development, we wondered whether the same iminoheterocycle chemotype could be used for inhibition of the related aspartyl protease renin. We were able to convince senior management at Schering-Plough to give us 6 months to come up with a renin inhibitor with good oral bioavailability, a property that was lacking in the successful renin inhibitor aliskiren. Knowing the extensive literature on the roles of the renin–angiotensin system in the brain, we were also interested to see what advantages a brain-penetrant renin inhibitor might have. By mining Schering-Plough’s BACE-1 inhibitor collection and carrying out rapid and creative lead optimization, Brian McKittrick and Tanweer Khan were able to discover potent and selective renin inhibitors such as inhibitor 6 (human renin Ki ¼ 0.6 nM).27 Having struggled with peptidomimetic renin inhibitors during 1980s, it was particularly gratifying to have this success over 25 years later. We wondered whether iminoheterocycles might prove to be a general scaffold for aspartyl protease inhibitors, and interestingly, a series of iminohydantoins have recently been reported which are potent inhibitors of the aspartyl protease plasmepsin, with potential for treatment of malaria.28 F H N N H N

H N

O O

Renin inhibitor 6

Throughout my career, I have been privileged to work with talented and dedicated scientists whose dream has been to contribute to the discovery of new medicines to reduce human suffering. Their commitment and persistence in the face of continual setbacks have been a source of inspiration. I am grateful for the support and encouragement that I have received from so many colleagues, and the opportunity to make a difference. There have been

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many changes since I joined Merck over 35 years ago. When I began as a new medicinal chemist there, I had every expectation that I would be at Merck my entire career, and in the end I moved only a few miles away to Schering-Plough, and later had the chance to rejoin Merck after the merger. No chemist hired today can have the expectation of a long, secure career with a single company. News of layoffs of medicinal chemists has become so frequent that it is easy to become cynical about the future of medicinal chemistry as a career path. In spite of the new uncertainty, there has never been a more exciting time to be involved in drug discovery, and I believe that new targets and approaches in discovery research offer a bright future for medicinal chemists. What guidance can we offer to medicinal chemists in the industry now or contemplating a career there? Here are my words of advice: (1) Do your best, stay focused on drug discovery, and work hard to gain a deep and critical understanding of medicinal chemistry. Expand your reading beyond chemistry to acquire a basic knowledge of related disciplines such as pharmacology, drug metabolism, and toxicology. (2) Build your resume and try to get one publication, presentation, and patent (at least) from each project you contribute to, so that your contributions can be recognized. Do not put off writing the paper, even if you are busy with the next project. (3) Find ways to contribute more to your projects and to medicinal chemistry. Become an expert on an important topic and write a review. Look for opportunities to become involved in medicinal chemistry outside your company, including volunteering in support of the American Chemical Society. (4) Above all, maintain a sense of urgency in your work, since what you are doing is important to the lives of patients. Remember that you have limited time in your career to make a difference, and take advantage of your opportunities. I wish you success and happiness in your efforts.

ACKNOWLEDGMENTS I would like to acknowledge the many outstanding colleagues who have contributed so much to my career in medicinal chemistry. I have mentioned just a few in the text, without the intention to overlook others. In addition, I would like to acknowledge Ashit Ganguly, Michael Czarniecki, Duane Burnett, Deen Tulshian, John Clader, Stuart McCombie, Cecil Pickett, Ismail Kola, Ann Weber, and Malcolm MacCoss.

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3. Patchett, A. A.; Harris, E.; Tristram, E. W.; Wyvratt, M. J.; Wu, M. T.; Taub, D.; Peterson, E. R.; Ikeler, T. J.; ten Broeke, J.; Payne, L. G.; Ondeyka, D. L.; Thorsett, E. D.; Greenlee, W. J.; Lohr, N. S.; Hoffsommer, R. D.; Joshua, H.; Ruyle, W. V.; Rothrock, J. W.; Aster, S. D.; Maycock, A. L.; Robinson, F. M.; Hirschmann, R. Nature 1980, 288, 280. 4. Weber, A. E.; Halgren, T. A.; Doyle, J. J.; Lynch, R. J.; Siegl, P. K. S.; Parsons, W. H.; Greenlee, W. J.; Patchett, A. A. J. Med. Chem. 1991, 34, 2692. 5. Maibaum, J.; Stutz, S.; G€ oschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.; Fuhrer, W.; Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832. 6. Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl, P. K. S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.; Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1991, 34, 2919. 7. Chakravarty, P. K.; Naylor, E. M.; Chen, A.; Chang, R. S. L.; Chen, T.-B.; Faust, K. A.; Lotti, V. J.; Kivlighn, S. D.; Gable, R. A.; Zingaro, G. J.; Schorn, T. W.; Schaffer, L. W.; Broten, T. P.; Siegl, P. K. S.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1994, 37, 4068. 8. Kivlighn, S. D.; Zingaro, G. J.; Gabel, R. A.; Broten, T. P.; Chang, R. S. L.; Ondeyka, D. L.; Mantlo, N. B.; Gibson, R. E.; Greenlee, W. J.; Siegl, P. K. Eur. J. Pharmacol. 1995, 294, 439. 9. Kivlighn, S. D.; Zingaro, G. J.; Rivero, R. A.; Huckle, W. R.; Lotti, V. J.; Chang, R. S. L.; Schorn, T. W.; Kevin, N.; Johnson, R. G., Jr.; Greenlee, W. J.; Siegl, P. K. S. Am. J. Physiol. 1995, 268, R820. 10. Perlman, S.; Costa-Neto, C. M.; Miyakawa, A. A.; Schambye, H. T.; Hjorth, S. A.; Paiva, A. C. M.; Rivero, R. A.; Greenlee, W. J.; Schwartz, T. W. Mol. Pharmacol. 1997, 51, 301. 11. Wan, Y.; Wallinder, C.; Plouffe, B.; Beaudry, H.; Mahalingam, A. K.; Wu, X.; Johansson, B.; Holm, M.; Botoros, M.; Karlen, A.; Pettersson, A.; Nyberg, F.; Fandriks, L.; Gallo-Payet, N.; Hallberg, A.; Alterman, M. J. Med. Chem. 2004, 47, 5995. 12. Williams, D. L., Jr.; Murphy, K. L.; Nolan, N. A.; O’Brien, J. A.; Pettibone, D. J.; Kivlighn, S. D.; Krause, S. M.; Lis, E. V., Jr.; Zingaro, G. J.; Gabel, R. A.; Clayton, F. C.; Siegl, P. K. S.; Zhang, K.; Naue, J.; Vyas, K.; Walsh, T. F.; Fitch, F. K.; Chakravarty, P. K.; Greenlee, W. J.; Clineschmidt, B. V. J. Pharmacol. Exp. Ther. 1995, 275, 1518. 13. Walsh, T. F.; Fitch, K. J.; Williams, D. L., Jr.; Murphy, K. L.; Nolan, N. A.; Pettibone, D. J.; Chang, R. S. L.; O’Malley, S. S.; Clineschmidt, B. V.; Veber, D. F.; Greenlee, W. J. Bioorg. Med. Chem. Lett. 1995, 5, 1155. 14. Murugesan, N.; Gu, Z.; Fadnis, L.; Tellew, J. E.; Baska, R. A. F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; Dickinson, K. E.; Valentine, M. T.; Humphreys, W. G.; Lan, S.-J.; Ewing, W. R.; Carlson, K. E.; Kowala, M. C.; Zahler, R.; Macor, J. E. J. Med. Chem. 1995, 48, 171. 15. Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Pineda de las Infantas y Villatoro, M. J.; Zocchi, C.; Dionisotti, S.; Ongini, E. J. Med. Chem. 1996, 39, 1164. 16. Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. ACS Chem. Neurosci. 2010, 1, 435. 17. Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford, A. W.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Ng, K.; Feng, K.-I. Bioorg. Med. Chem. Lett. 2007, 17, 1376. 18. Chackalamannil, S.; Wang, Y.; Greenlee, W. J.; Hu, Z.; Xia, Y.; Ahn, H.-S.; Boykow, G.; Hsieh, Y.; Palamanda, J.; Agans-Fantuzzi, J.; Kurowski, S.; Graziano, M.; Chintala, M. J. Med. Chem. 2008, 51, 3061. 19. http://www.mercknewsroom.com/press-release/research-and-development-news/ merck-announces-fda-acceptance-new-drug-application-vora.

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