Successful Drug Discovery, Volume 1 (eBook)

János Fischer, David P. Rotella (Herausgeber)

eBook Download: EPUB

2015
Wiley-VCH (Verlag)
978-3-527-67845-7 (ISBN)

Infos

The first volume of the book series 'Successful Drug Discovery' is focusing on new drug discoveries during the last decade, from established drugs to recently introduced drugs of all kinds: small-molecule-, peptide-, and protein-based drugs.
The role of serendipity is analyzed in some very successful drugs where the research targets of the lead molecule and the drug are different. Phenotypic and target-based drug discovery approaches are discussed from the viewpoint of pioneer drugs and analogues.
This volume gives an excellent overview of insulin analogues including a discussion of the properties of rapid-acting and long-acting formulations of this important hormone.
The major part of the book is devoted to case histories of new drug discoveries described by their key inventors. Eight case histories range across many therapeutic fields.
The goal of this book series is to help the participants of the drug research community with a reference book series and to support teaching in medicinal chemistry with case histories and review articles of new drugs.


Janos Fischer is a Senior Research Scientist at Richter Plc., Budapest, Hungary. He received his MSc and PhD degrees in organic chemistry from the Eotvos University of Budapest under Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn under Professor W. Steglich. He has worked at Richter Plc. since 1981 where he participated in the research and development of leading cardiovascular drugs in Hungary. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.
David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he became an assistant professor at the University of Mississippi. Before accepting his current position he worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

Autor

János Fischer is a Senior Research Scientist at Richter Plc., Budapest, Hungary. He received his MSc and PhD degrees in organic chemistry from the Eotvos University of Budapest under Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn under Professor W. Steglich. He has worked at Richter Plc. since 1981 where he participated in the research and development of leading cardiovascular drugs in Hungary. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest. David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he became an assistant professor at the University of Mississippi. Before accepting his current position he worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

Inhalt

GENERAL ASPECTS
Serendipitious Target-based Drug Discoveries
Drug Discoveries and Molecular Mechanism of Action
DRUG CLASSES
Insulin Analogues Improving the Therapy of Diabetes
CASE HISTORIES
The Discovery of StendraTM (Avanafil) for the Treatment of Erectile Dysfunction
Dapagliflozin, a Selective SGLT2 Inhibitor for Treatment of Diabetes
Elvitegravir, a New HIV-1 Integrase Inhibitor for Antiretrovial Therapy
Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus
The Discovery of Alimta (Pemetrexed)
Perampanel: a Novel, Non-competitive AMPA Receptor Antagonist for the Treatment of Epilepsy
Discovery and Development of Telaprevir (IncivekTM) - a Protease Inhibitor to Treat Hepatitis C Infection
Antibody-Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1)

Textauszug

Chapter 1
Serendipitous Target-Based Drug Discoveries

János Fischer and David P. Rotella

1.1 Introduction

Breakthrough drug discoveries – based on a molecular biological target – can significantly improve therapy for disease. For example, captopril (discovered in 1976) is a pioneer angiotensin-converting enzyme (ACE)-inhibitor used for treatment of essential hypertension. Subsequent compounds acting on the same target (e.g., enalapril, lisinopril, and perindopril) are used for the same purpose. An alternative and complementary treatment for hypertension involves use of angiotension II receptor antagonists. Losartan (discovered in 1986) was the first compound in this class and was followed by several additional molecules (e.g., valsartan, telmisartan, and irbesartan). Treatment of hypertension by these mechanisms provided physicians with additional options to consider as a part of combination therapy or when other possibilities such as diuretics and/or β-blockers are unsatisfactory. For the treatment of obstructive airway diseases several short and long-acting β-2-adrenoreceptor agonists (e.g., salbutamol, formoterol, and salmeterol) that act directly on lung tissue to improve airway function have been discovered. Antimuscarinics selective for M1 and M3 receptors such as tiotropium bromide (discovered in 1989) were found to be effective for treatment of chronic obstructive pulmonary disease (COPD). These distinct mechanisms of action can be used in combination to treat COPD and other complex airway disorders. Imatinib (discovered in 1992) is a BCR-Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) that demonstrated the concept of targeted chemotherapy substantially improving survival in this difficult to treat disease. In the field of metabolic diseases, sitagliptin (discovered in 2001) was the first dipeptidyl peptidase-IV (DPP-IV) inhibitor for the treatment of type 2 diabetes. The recognition that inhibition of this enzyme could prolong the serum half life of glucagon-like peptide-1 (GLP-1), a peptide hormone that helps tightly regulate blood sugar without substantial risk of hypoglycemia, provided physicians, and patients with another effective mechanistic option for treatment of type 2 diabetes.

1.2 Recent Examples of Target-Based Drug Discovery

In contemporary drug discovery, a key feature to help maximize the chance for success (i.e., marketing approval) is a clear understanding of the molecular target and mechanism of action for a drug candidate. Contributions to this volume describe the rationale for target selection, association(s) with the disease, and in some cases clinical biomarkers that provide critical information on target engagement as well as the correlation between dose and effect pharmacokinetic/pharmacodynamic (PK/PD) effects. This approach allows the discovery team to test a hypothesis for a first-in-class drug candidate. For a follow-on program where previous experience provides the necessary background, it may prove necessary to investigate aspects such as selectivity or adverse events that were not appreciated or were incompletely understood with the initial molecule.

For example, the discovery of dapagliflozin, the first sodium-glucose transporter type 2 (SGLT2) inhibitor approved for use in the treatment of type 2 diabetes, had a clear mechanism and target. By preventing reabsorption of glucose in the kidney, lower blood sugar could result. Approximately 90% of glucose reabsorption occurs in the kidney, and by promoting glucose excretion, lowered blood sugar should result. Lowering blood glucose is an indicator of target engagement that is also a clinically relevant biomarker for efficacy. This mechanism of action has a low risk of hypoglycemia because it is independent of insulin secretion, providing clinicians with a useful option to use in combination with metformin or insulin. Clinical trials revealed that SGLT2 inhibition could also lead to weight loss and improved plasma lipid profiles. Each of these unanticipated (based on the mechanism of action) effects are welcome benefits in type 2 diabetic patients because of other comorbidities including obesity, atherosclerosis, and hyperlipidemia. Combination studies of SGLT2 inhibitors with other diabetes treatments are underway, including use with DPP4 inhibitors. Given the complexity of type 2 diabetes, addition of another validated mechanism to treat the disease, especially one that can be used effectively in combination with others, is a true advance in the treatment of a serious and widespread disease.

The introduction of trastuzumab emtansine for treatment of metastatic breast cancer represents a particularly interesting example of a combination of a small molecule cytotoxic agent DM1 and the antibody trastuzumab that recognizes the human epidermal growth factor receptor 2 (HER2) receptor specifically expressed in breast cancer cells. In spite of the utility of the antibody alone for treatment of the disease, not all HER2 positive tumors respond, and some patients become refractive. While trastuzumab exerts its effect via more than one mechanism, the appeal of targeted delivery of a potent cytotoxic agent has potential advantages for therapeutic efficacy. Selective delivery only to cancer cells continues to be one of the limitations associated with use of cytotoxic agents in oncology that is most difficult to overcome. DM1 is a microtubule binding agent that is 3–10 times more potent in vitro compared to the well studied derivative maytansine, and up to 500 times more potent compared to the widely used taxanes. High potency for the small molecule target was recognized to be an important goal because of dose limiting toxicities. This antibody–drug conjugate employs two distinct and complementary mechanisms to achieve these goals, providing patients and clinicians facing metastatic breast cancer with a potentially useful option.

The approval of sofosbuvir (Sovaldi®) (Figure 1.1) in 2013, a viral ribonucleic acid (RNA) polymerase inhibitor used in combination with ribavarin represents the first all oral therapy for treatment of hepatitis C viral (HCV) infection. This chronic disease was initially treated with a combination of injectable interferon and ribavarin and was associated with significant adverse events, and it was also inconvenient for patients because one of the drugs had to be injected and the extended therapeutic course had to be an extended one (∼52 weeks) to achieve maximal efficacy. Against this therapeutic backdrop for a disease that affects over 150 million people worldwide, a number of alternative approaches with specific molecular targets associated with the virus are being investigated. Foremost among these are two proteases, NS3A/NS4A, along with viral RNA polymerase. Polymerase approaches for viral diseases are being very actively investigated; however, they frequently suffer from low potency because the molecule must be converted to a triphosphate derivative in cells. The first step in this process is slow and rate limiting, which results in reduced efficacy. Sofosbuvir is a monophosphate prodrug of a modified nucleoside that can bypass the slow initial phosphorylation step. The molecule is rapidly converted to a triphosphate derivative, which is a potent inhibitor of the viral enzyme. Clinical studies with sofosbuvir revealed that a sustained viral response could be achieved rapidly (in as short as 24 weeks) in combination with ribavarin. This substantially reduces the time course of therapy, is associated with fewer adverse events, and can be more easily administered because it is an all-oral regimen.

Figure 1.1 Sofosbuvir (Sovaldi).

Treatment of rheumatoid arthritis is dominated by a number of biologics that require periodic injections. These therapies, while beneficial and effective, are recognized to be less convenient compared to oral administration of a small molecule. A number of approaches have been investigated to identify suitable molecular targets and small molecules for this purpose. In 2012, the approval of tofacitinib (Figure 1.2) represented the first small molecule since methotrexate to be approved for treatment of this crippling progressive disorder. Tofacitinib inhibits Janus kinase 3 (JAK3), an intracellular tyrosine kinase that plays a role in signal transduction associated with a number of proinflammatory cytokines. JAK3 is localized in lymphocytes; analysis of plasma in rheumatoid arthritis patients showed that high levels of the kinase were present in the synovial fluid. This link between pathology and the site of action (i.e., the joint) provided reasonable assurance that inhibition of the enzyme represented a mechanistically reasonable approach for treatment of this disease. Kinase selectivity was a key objective to address because inhibition of JAK1 and/or JAK2 was undesirable because of potential toxicity. Clinical studies revealed that the molecule was effective as monotherapy and had an acceptable safety profile. More recently, Phase 2 and 3 combination studies with methotrexate showed efficacy in patients who did not respond to other anti-TNF (tumor necrosis factor) therapies such as adalimumab.

Figure 1.2 Tofacitinib (Xeljanz).

In early 2014, a novel small molecule was approved for treatment of psoriatic arthritis. Apremilast (Figure 1.3) is an inhibitor of phosphodiesterase 4 (PDE4), a well known enzyme that has been studied for a number of years. It was well known that inhibition of this cyclic nucleotide hydrolase elevated local concentration of cyclic AMP, an important second...

Produkt-Details

• Erscheint lt. Verlag: 30.1.2015
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie
• Themenwelt: Technik
• Schlagworte: Biopharmaceuticals & Pharmaceutical Biotechnology • Biopharmazeutika u. Pharmazeutische Biotechnologie • Chemie • Chemistry • Drug Discovery & Development • Organic Chemistry • Organische Chemie • small molecule drug biological biopharmaceutics serendipity Avanafil Dapagliflozin Elvitegravir Linagliptin Pemetrexed Perampanel Telaprevir Trastuzumab Emtansine • Wirkstoffforschung • Wirkstoffforschung u. -entwicklung
• ISBN-10: 3-527-67845-X / 352767845X
• ISBN-13: 978-3-527-67845-7 / 9783527678457