Perspective Cite This: J. Med. Chem. 2018, 61, 10996−11020 pubs.acs.org/jmc From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen Heterocycles Michael D. Delost, David T. Smith, Benton J. Anderson, and Jon T. Njardarson* Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, Arizona 85721, United States ABSTRACT: Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals. Analysis of our database of drugs approved through 2017 reveals 311 distinct pharmaceuticals containing at least one oxygen heterocycle. Most prevalent among these are pyranoses, with furanoses, macrolactones, morpholines, and dioxolanes rounding off the top five. The main body of this Perspective is organized according to ring size, commencing with three- and four-membered rings and ending with macrocycles, polymers, and unusual oxygen- containing heterocycles. For each section, all oxygen hetero- cycle-containing drugs are presented along with a brief discussion about structural and drug application patterns. ■ INTRODUCTION Inspired by how much was learned by assembling and analyzing the 640 small molecule drugs containing nitrogen heterocycles1 as well as other educational endeavors,2 a similar study for oxygen heterocycles has now been completed. Analysis of our drug database (through 2017) unearthed a total of 311 unique oxygen heterocycle-containing pharmaceuticals, which is a significant representation (about 27% of unique approved small molecules and 15% of all approved drugs). In comparison, our group’s 2016 top 200 pharmaceutical prescription and retail sales posters reveal 17% and 16% representation of oxygen- heterocycle containing pharmaceuticals, respectively.3 Many of Downloaded via UNIV OF ARIZONA on August 6, 2021 at 17:18:02 (UTC). these drugs contain more than one oxygen heterocycle with a total of 389 oxygen heterocycles being part of these 311 drugs. Figure 1. Distribution of oxygen heterocycles according to ring size and For example, recently approved eteplirsen and mipomersen aromaticity. contain 30 and 20 oxygen heterocycles, respectively. In the See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. context of the evolutionarily selected structures carbohydrates ff fi and nucleosides, it is unsurprising that pyranoses and furanoses representation, respectively. Rounding o the top ve are are the top two most frequently employed oxygen heterocycles. macrocycles (10%) followed by three-membered (3%), seven- In this Perspective, all 311 U.S. FDA approved drugs containing membered (2%), and four-membered (1%) rings. oxygen heterocycles are presented, analyzed, and discussed in A closer look at the 311 unique oxygen heterocycle containing sections organized according to ring size or unique common U.S. FDA approved drugs reveals the majority (71%) are structural features. substituted with only one oxygen heterocycle (Figure 2), with The breakdown of the 389 oxygen heterocycles that are 13% and 6% consisting of two and three oxygen heterocycles, components of the 311 identified oxygen heterocyclic drugs is respectively. A decent number (3%) of these drugs are decorated presented according to ring size and presence or absence of with greater than eight oxygen heterocycles. Although the aromaticity in Figure 1. The majority (89%) of the oxygen atomic composition of the rings of these oxygen heterocycles fi primarily comprises one oxygen atom and carbon atoms (64%) heterocycles are nonaromatic; 95% of aromatic are ve- fi membered rings. These numbers are significantly higher than as one would nd in pyranoses, furanoses, etc., a large number for their nitrogen heterocyclic counterparts where 70% are (26%) also contain nitrogen, sulfur, boron, and even metal nonaromatic and 60% of the aromatic heterocycles are five- membered rings. With respect to ring size, five- and six- Received: June 2, 2018 membered rings reign supreme (84% total) with 46% and 38% Published: July 19, 2018 © 2018 American Chemical Society 10996 DOI: 10.1021/acs.jmedchem.8b00876 J. Med. Chem. 2018, 61, 10996−11020 Journal of Medicinal Chemistry Perspective Figure 2. Frequency and structural content of oxygen heterocycles. Figure 3. Most frequent oxygen heterocycles in U.S. FDA approved drugs. atoms, and 10% contain a second oxygen atom. The most drugs revealed that pyranoses are number 1 with 62 appearances common of these are rings composed of one oxygen and one (16%) followed by furanoses in a distant second place (9%). nitrogen atom, which are represented by members such as Macrolactones, morpholines, and dioxolanes account for the oxazoles and morpholines and their isomeric variants. Finally, remaining top five. These data for oxygen heterocycles are far most (75%) of these oxygen heterocycles are chiral. more top heavy in favor of one heterocycle (pyranose) when Our analysis led us to identify the top 27 most frequently compared with nitrogen heterocycles, with a 45% decrease occurring oxygen heterocycles in the FDA pharmaceutical between #1 (pyranose) and #2 (furanose) compared to 14% library (Figure 3). Analysis of the 389 oxygen heterocycles drop between (#1) piperidine and (#2) pyridine. In assembling contained within the 311 unique oxygen heterocycle-containing this top 27 list and deciding how to best convey the diversity of 10997 DOI: 10.1021/acs.jmedchem.8b00876 J. Med. Chem. 2018, 61, 10996−11020 Journal of Medicinal Chemistry Perspective Figure 4. Pharmaceuticals containing oxiranes. oxygen heterocycles presented in later sections, similar ring structures, drugs that contain more than one oxygen heterocycle types are organized according to their degree and location of appear in more than one section. For each section, the oxygen unsaturation as well as exact location of heteroatoms within a heterocycle of focus is highlighted in blue and drug structures are given ring and fusion with other rings. For example, pyranoses organized based on common disease indications. For drug are not the only six-membered rings containing a single oxygen families with high structural similarity, alphabetized colored atom in the top 27. Also belonging to this broad category would circles are employed to signify structural deviations from the be tetrahydropyrans, chromenes, chromanes, δ-lactones, and common core. dihydropyrans. Similarly, isoxazole and oxazole were categorized separately. Macrolactones (#3) make it into the top 10, which is ■ THREE-MEMBERED OXYGEN HETEROCYCLES in stark contrast to nitrogen heterocycles, for which no Oxiranes appear in 13 U.S. FDA approved drugs (Figure 4). macrocycles make it into the top 27. This is perhaps not With respect to oxirane substitution arrangements, only di- entirely surprising as macrocyclic drugs are commonly natural (69%) and trisubstituted oxiranes are represented. Three of the products or derivatives that usually contain 14- to 20-membered trisubstituted rings are part of fused natural product-type ring lactones. Dioxolanes, which chemists typically associate with # systems (eplerenone, trilostane, and picrotoxin), while one carbonyl protecting groups, are quite a surprise at 5 being part (ixabepilone) is nonfused. The disubstituted oxiranes can be of 24 approved drugs. Oxiranes appear highly on this list; this is further broken down into three categories: 1,1-disubstituted not the case for the three-membered nitrogen heterocycle (carfilzomib and troleandomycin), 1,2-trans-disubstituted (na- aziridine, which is only seen in a single U.S. FDA approved drug. tamycin and mupirocin), and 1,2-cis-disubstituted (scopol- Only 5 (19%) of the top 27 oxygen heterocycles are aromatic, amine, methyl scopolamine, tiotropium, cerulenin, and # with isoxazole ( 6) being the most commonly occurring. Two fosfomycin). These oxirane-containing drugs are structurally − (1,3-oxathiolane and boron oxygen heterocycles) of these top diverse with origins in natural products. Troleandomycin, structures contain atoms other than carbon, oxygen, or nitrogen natamycin, mupirocin, scopolamine, and picrotoxin are natural as part of their rings. Four fused ring types (morphine, products, while eplerenone, trilostane, tiotropium, and methyl chromene, benzofuran, and chromane) are represented, which scopolamine are natural products derived from steroids and is far fewer than for nitrogen heterocycles where 11 fused rings tropanes, respectively. Scopolamine, methyl scopolamine, and are highly ranked. Oxadiazoles are the only oxygen heterocycle tiotropium are anticholinergic drugs used to treat a variety of in the top 27 with two additional heteroatoms as part of the core conditions such as nausea, peptic ulcers, irritable bowel ring. Furthermore, 13 (48%) of the top 27 oxygen heterocycles syndrome, and chronic obstructive pulmonary disease are five-membered; 8 (30%) are six-membered. (COPD).4,5 These drugs are easily recognizable by their tropane In the sections that follow, all of the 311 unique oxygen ring. Fosfomycin, isolated from Streptomyces fradiae, is a broad- heterocycle-containing drugs are presented according to their spectrum antibiotic effective against both Gram-negative and ring size, from small to large starting with oxiranes and Gram-positive bacteria. Intriguingly, fosfomycin, with its small continuing all the way to macrocyclic structures, with the final size and phosphonic acid substitution at a reactive oxirane