Put a ring on it: application of small aliphatic rings in medicinal chemistry

Author(s): Matthias R. Bauer ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Paolo Di Fruscia ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Simon C. C. Lucas ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Iacovos N. Michaelides ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Jennifer E. Nelson ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , R. Ian Storer ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ , Benjamin C. Whitehurst ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵

Publication date (Electronic): 2021

Journal: RSC Medicinal Chemistry

Publisher: Royal Society of Chemistry (RSC)

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Abstract

Aliphatic small rings including cyclopropanes, cyclobutanes, oxetanes, azetidines and bicyclo[1.1.1]pentanes have been increasingly exploited in medicinal chemistry. This review summarises judicious successful application and reported limitations of these ring systems.

Abstract

Aliphatic three- and four-membered rings including cyclopropanes, cyclobutanes, oxetanes, azetidines and bicyclo[1.1.1]pentanes have been increasingly exploited in medicinal chemistry for their beneficial physicochemical properties and applications as functional group bioisosteres. This review provides a historical perspective and comparative up to date overview of commonly applied small rings, exemplifying key principles with recent literature examples. In addition to describing the merits and advantages of each ring system, potential hazards and liabilities are also illustrated and explained, including any significant chemical or metabolic stability and toxicity risks.

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Most cited references 179

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Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals.

Edon Vitaku, David Smith, Jon Njardarson (2014)

Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.

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Escape from flatland: increasing saturation as an approach to improving clinical success.

Frank Lovering, Jack Bikker, Christine Humblet (2009)

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.

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Synopsis of some recent tactical application of bioisosteres in drug design.

Nicholas Meanwell (2011)

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Author and article information

Contributors

Simon C. C. Lucas: (View ORCID Profile)

Iacovos N. Michaelides: (View ORCID Profile)

Jennifer E. Nelson: (View ORCID Profile)

Benjamin C. Whitehurst: (View ORCID Profile)

Journal

Journal ID (publisher-id): RMCSCX

Title: RSC Medicinal Chemistry

Abbreviated Title: RSC Med. Chem.

Publisher: Royal Society of Chemistry (RSC)

ISSN (Electronic): 2632-8682

Publication date Created: 2021

Publication date (Electronic): 2021

Affiliations

[1 ]Discovery Sciences

[2 ]BioPharmaceuticals R&D

[3 ]AstraZeneca

[4 ]Cambridge

[5 ]UK

Article

DOI: 10.1039/D0MD00370K

PubMed ID: 33937776

SO-VID: f31b81b9-9a6b-4bbe-8efb-b63bb1e41eb6

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http://rsc.li/journals-terms-of-use

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