Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,...

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Published inJournal of medicinal chemistry Vol. 63; no. 22; pp. 13389 - 13396
Main Authors Nilova, Aleksandra, Campeau, Louis-Charles, Sherer, Edward C, Stuart, David R
Format Journal Article
LanguageEnglish
Published United States 25.11.2020
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Abstract Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists. Finally, we calculated medicinal chemistry properties of benzenoid containing APIs that are often used by practitioners as design elements, including "druglikeness", shape, complexity, and similarity/diversity and discuss these properties in the context of synthesis.
AbstractList Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution patterns of benzenoid rings in small molecule APIs approved by the FDA through 2019 and show that only a few substitution patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution has remained relatively constant over time. We postulate the connection between available synthetic methods and the occurrence of a few benzenoid substitution patterns by providing an overview of synthetic methods that elaborate existing substitution patterns and those that create new substitution patterns, including those of the former that are favored by medicinal chemists. Finally, we calculated medicinal chemistry properties of benzenoid containing APIs that are often used by practitioners as design elements, including "druglikeness", shape, complexity, and similarity/diversity and discuss these properties in the context of synthesis.
Author Campeau, Louis-Charles
Nilova, Aleksandra
Stuart, David R
Sherer, Edward C
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  surname: Campeau
  fullname: Campeau, Louis-Charles
  organization: Process Research and Development, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States
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  orcidid: 0000-0001-8178-9186
  surname: Sherer
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  orcidid: 0000-0003-3519-9067
  surname: Stuart
  fullname: Stuart, David R
  organization: Department of Chemistry, Portland State University, Portland, Oregon 97201, United States
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Snippet Previous analyses have revealed that benzenoid rings are prevalent scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze the substitution...
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StartPage 13389
SubjectTerms Benzene Derivatives - analysis
Benzene Derivatives - chemistry
Chemistry, Pharmaceutical - methods
Chemistry, Pharmaceutical - trends
Databases, Factual - trends
Pharmaceutical Preparations - analysis
Pharmaceutical Preparations - chemistry
Title Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients
URI https://www.ncbi.nlm.nih.gov/pubmed/32786676
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