Rings in Drugs

Abstract

We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, timelines, molecular property space, and the application of these rings in different therapeutic areas and target classes. This analysis shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on average six new ring systems enter drug space each year and approximately 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.

New heteroatom-rich ring systems from N,N-dialkyl-N’-chlorosulfonyl chloroformamidines

“…However, it is known that the exocyclic nitrogen atom of 2-aminothiazoles is the preferred site of reaction with sp 2 C electrophiles (e.g. acid chlorides, formimidates) 34,35 while the N-3 atom of 2-amino[1, 3,4]thiadiazoles has greater nucleophilicity than the exocyclic nitrogen atom, 36 so the findings described above provide consistent evidence that the chloro-substituted amidine carbon atom of 1 is the more electrophilic site.…”

“…43 Further experiments were conducted to test the nucleophilicity of the NH moiety of the novel heterocyclic system 40 towards acylation. These involved the use of acetyl or benzoyl chloride in the absence of pyridine or with a non-nucleophilic base, or Friedel-Crafts conditions employing BF 3 .OEt 2 as a Lewis acid catalyst, as well as carbodiimide/activated ester coupling methodology with simple carboxylic acids. No useful reactions were observed under a variety of conditions.…”

“…Nitrogen-containing rings are also common fragments of the majority of marketed drugs [2][3][4] and the reason for this is that identification of effective therapeutic treatments is usually based on mimicking nature but "fooling" it in a very subtle way. Because heterocycles are core elements of a wide range of natural products such as nucleic acids, amino acids, vitamins, and alkaloids, medicinal chemistry discovery efforts often evolve around simulating such structural motifs.…”

“…2 Heterocycles also play a larger role in medicinal chemistry. The strategic inclusion of a heterocyclic moiety into a drug candidate molecule can allow the modulation of properties 2, 3,[5][6][7][8][9] such as potency and selectivity (through bioisosteric replacements), lipophilicity, polarity, aqueous solubility, electronic distribution, hydrogen bond basicity, and metabolic stability. Replacement of carbo-aromatic rings with hetero-aromatic rings and inclusion of fused ring systems rather than individual rings tends to confer reduced lipophilicity and greater aqueous solubility, resulting in improved properties.…”

“…4 It has been widely concluded that the number of ring systems in drugs and bioactive space is currently very small and distributed in sparsely populated islands. 3 The historical exploration of chemical space by synthetic chemists has been exceptionally uneven and unsystematic. Around half of all known compounds are based on just 0.25% of the known molecular scaffolds and this uneven exploration is also reflected in small molecule screening collections.…”