Drug Discovery with Privileged Building Blocks

Tactics in Medicinal Chemistry

Jie Jack Li, Minmin Yang

• Publisher: CRC Press
• Year: 2021
• Print ISBN: 9781032041681
• eBook ISBN: 9781000416060
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Drug Discovery with Privileged Building Blocks traces back PharmaBlock's founding philosophy of designing privileged building blocks. High-quality building blocks are crucial not only to biological activities of different molecules but also to ADMET properties, which eventually will impact the success rate of drug discovery projects. A thorough study of how building blocks perform in drug molecules and a regular analysis of new building block structures in the latest researches have proven to be a fruitful strategy to generate novel building blocks. Using this strategy, PharmaBlock has supplied the drug industry with a great number of building blocks, which are increasingly being adopted by drug hunters, and these are identified in this book.

Each chapter may be read and studied without learning the previous chapters. This book will be a good starting point for novice medicinal chemists, and veteran medicinal chemists will find it useful as well.

Key Feature

• The book covers privileged building blocks appearing most frequently on patents for novel drugs.

• The latest relevant tactics are explained in the context of drug design and medicinal chemistry.

• Key synthesis, especially large-scale synthesis, is described.

• The most recent literature references are cited.

1 Alkynes

The alkyne fragment may be found in approximately two dozen drugs on the market in a variety of therapeutic areas. Despite being a structural alert, giving rise to reactive metabolites on occasions, the alkyne motif has a special place in drug discovery, serving as a unique bioisostere for many functional groups such as halogen, nitrile, carboxamide, ethyl, and so on; non-polar rigid and sterically less demanding spacers; and a part of a warhead of targeted covalent inhibitors.

Alkyne-Containing Drugs

Marketed in the late 1950s, the alkyne-containing drug norethindrone (Norlutin, 1) was revolutionary as the first oral contraceptive pill working as a progesterone receptor antagonist.¹ Afterward, approximately a dozen “me-too” alkyne-containing steroid drugs followed as birth control pills. More successful ones include Roussel Uclaf’s mifepristone (Korlym, RU486, 2),² Schering’s ethinyl estradiol (Yaz in combination with drospirenone), levonorgestrel (Liletta, Plan B) as an emergency birth control pill, and so on. Mifepristone (2) is also a mechanism-based inhibitor (MBI) of CYP 3A4 apoprotein and its alkyne motif is implicated as a ketene precursor during metabolism.

Alkyne-containing drug selegiline [(–)-deprenyl, Eldepryl, 3], a weak and selective inhibitor of monoamine oxidase-B (MAO-B), was marketed by Knoll in 1971 as an antidepressant.³ Now it has been explored in the transdermal treatment of neurodegenerative disorders and neurological diseases such as Parkinson’s and Alzheimer’s diseases. On the other hand, Novartis’s terbinafine (Lamisil, 4) is an orally and topically active hindered alkyne-containing allylamine antifungal agent. It is a squalene epoxidase inhibitor.⁴ Terbinafine (4) causes rare cases of hepatotoxicity possibly because it undergoes N-dealkylation to a reactive iminium and an aldehyde.

Alkyne-containing tazarotene (Tazorac, 5) is developed by Allergan as a treatment for acne vulgaris. It is a topical receptor-selective retinoid that normalizes the differentiation and proliferation of keratinocytes. Its major metabolite, tazarotenic acid, binds to retinoic acid receptors (RARs) with high affinity.⁵ Like most topically administered retinoids, tazarotene (5) may avoid some of those drawbacks including teratogenicity by systemically administered retinoids such as isotretinoin (Accutane). On the other hand, efavirenz (Sustiva, 6) is an alkyne-containing non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by BMS/Merck for the treatment of AIDS.⁶ It is an ingredient of the cocktail treatment of HIV along with a protease inhibitor (PI), and a nucleoside reverse transcriptase inhibitor (NRTI).

Some additional alkyne-containing drugs emerged in the 2000s. Schering’s iloprost (Ilomedine, 7) is an analog of prostacyclin (epoprostenol, PGI₂, produced in the vascular endothelium) with improved metabolic and chemical stability. It is a platelet aggregation inhibitor prescribed for the treatment of peripheral vascular diseases.⁷ Inhaled iloprost (7) has been used for the treatment of primary pulmonary hypertension (PPH). In addition, among more than 60 protein kinase inhibitors on the market today, one of the only two alkyne-containing drugs is erlotinib (Tarceva, 8), which is an epithelial growth factor receptor (EGFR) kinase inhibitor approved for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer.⁸ The other alkyne-containing kinase inhibitor is ponatinib (Iclusig, 33, vide infra).

Allos’s pralatrexate (Folotyn, 9) is an antifolate antimetabolite approved by the FDA in 2009 for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).⁹ In 2020, it received the orphan drug designation in the EU for the treatment of cutaneous T-cell lymphoma (CTCL). Its distinctive ethynylethyl motif is a bioisostere of the methylamine fragment of methotrexate, the prototype of this class of thymidylate inhibitors that block the functions of dihydrofolate reductase (DHFR). Given in its injectable form, pralatrexate (9) has a superior potency and toxicity profile to other DHFR inhibitors. For chemistry aficionados, the stereochemistry on C-10 is racemic, and thus pralatrexate (9) is a mixture of two diastereomers.

Approximately ten dipeptidyl peptidase-IV (DPP-4) inhibitors known as “gliptins” are currently on the market for the treatment of type II diabetes mellitus (T2DM). Boehringer Ingelheim’s orally active DPP-4 inhibitor linagliptin (Tradjenta, 10) was approved by the FDA in 2011. In vitro, linagliptin (10) has an IC₅₀ value of 1 nM, more potent than sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). Furthermore, linagliptin (10) also exhibited prolonged pharmacodynamic activity with long-lasting DDP-4 in several preclinical species.¹⁰

Recently, targeted covalent inhibitors have emerged as an exciting strategy to overcome the perpetual struggle against cancer cells’ drug resistance. Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase. Inhibition of BTK activity prevents downstream activation of the B-cell receptor (BCR) pathway and subsequently blocks cell growth, proliferation, and survival of malignant B cells. The second BTK inhibitor acalabrutinib (Calquence, 11) gained approval from regulatory agencies in 2017.¹¹ While it works through the same mechanism of action (MOA) as its progenitor ibrutinib (Imbruvica), acalabrutinib (11)’s warhead is a but-2-ynamide. Ibrutinib and acalabrutinib (11) are known as the first-generation BTK inhibitors. Although they can do wonders to cancer patients afflicted with B-cell malignancies, 75% of them develop resistance to them within 2 years. Close scrutiny revealed that a substitution of serine for cysteine at residue 481 (C481S) took place. Such a mutation led to a less nucleophilic serine so that the first-generation BTK inhibitors are no longer effective. Efforts are underway to discover the second-generation BTK inhibitors.

Alkynes in Drug Discovery

Hench and Kendall’s landmark discovery of cortisone (12) in the late 1940s heralded the steroid era. Isolation and later synthesis by Marker of progesterone (13) promoted research on its pharmacological properties in the treatment of menstrual disorders. Two features ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• Authors
• Chapter 1 Alkynes
• Chapter 2 Azaindoles
• Chapter 3 Azetidines
• Chapter 4 Bicyclic Pyridines Containing Ring-Junction N
• Chapter 5 Bicyclo[1.1.1]pentyl (BCP) as an sp3 Carbon-Rich Bioisostere for para-Phenyl and tert-Butyl Groups
• Chapter 6 Bicyclo[2.2.2]octane (BCO) as a 3D-Rich Bioisostere for the para-Phenyl Group
• Chapter 7 Bicyclo[3.1.0]hexanes
• Chapter 8 Bridge-Fused Rings as m-Phenyl Bioisosteres
• Chapter 9 Cubanes, Are We There Yet?
• Chapter 10 Cyclobutanes
• Chapter 11 Cyclohexanes
• Chapter 12 Cyclopentanes
• Chapter 13 Cyclopropane Derivatives as Metabolically More Robust Bioisosteres for Linear Alkyl Substituents
• Chapter 14 Deazapurines
• Chapter 15 Furopyridines
• Chapter 16 Indazoles
• Chapter 17 Indoles
• Chapter 18 Oxetanes
• Chapter 19 Piperidine, the Enchanted Ring
• Chapter 20 Pyrazines
• Chapter 21 Pyrazoles
• Chapter 22 Pyridazines
• Chapter 23 Pyridines—The Magic of Phenyl–Pyridyl Switch
• Chapter 24 Pyrimidines
• Chapter 25 Pyrrolidines
• Chapter 26 Pyrrolotriazines
• Chapter 27 Spiroazetidines
• Chapter 28 Spirocyclic Piperidines
• Chapter 29 Spirocyclic Pyrrolidines
• Chapter 30 Spirooxetanes
• Chapter 31 Tetrahydropyrans
• Chapter 32 Trifluoromethylpyridines
• Index