sp3-Rich Building Blocks as Bioisosteres of Benzene, Morpholine and Piperazine Rings

Planar molecules are more likely to fail in clinical trials, so TCI highlights building blocks that replace flat aromatic rings with sp3-rich bioisosteres.¹) Spiro oxetane-azetidine building block (O0466) is shown as a bioisostere of morpholine, while Boc-protected spiro building block (B5032), drawn from N-Boc-piperazine, serves as a piperazine bioisostere.²)³) Bicyclo[1.1.1]pentane amine building block (B5479) and Bicyclo[1.1.1]pentane mono-ester acid building block (M3149) act as benzene ring bioisosteres, as does Cubane diester building block (D5542).³)⁴)⁵) M3149 is also drawn in a tubulin polymerization inhibitor (tubulysin analog) structure, while O0466 appears in an MCHr1 antagonist structure. These blocks are expected to add sp3 carbon character, improving solubility and three-dimensionality of drug candidates.

Related products

• TCI O0466 174-78-7 2-Oxa-6-azaspiro[3.3]heptane
• TCI B5479 22287-35-0 Bicyclo[1.1.1]pentan-1-amine Hydrochloride
• TCI M3149 83249-10-9 3-(Methoxycarbonyl)bicyclo[111]pentane-1-carboxylic Acid
• TCI D5542 29412-62-2 Dimethyl Cubane-1,4-dicarboxylate
• TCI B5032 1041026-70-3 tert-Butyl 2,6-Diazaspiro[3.3]heptane-2-carboxylate

References

1. F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752. doi:https://doi.org/10.1021/jm901241e
2. G. Wuitschik, M. Rogers-Evans, K. Müller, E. M. Carreira, et al., Angew. Chem. Int. Ed. 2008, 47, 4512. doi:https://doi.org/10.1002/anie.200800450
3. J. Burkhard, E. M. Carreira, Org. Lett. 2008, 10, 3525. doi:https://doi.org/10.1021/ol801293f
4. J. M. Lopchuk, P. S. Baran, et al., J. Am. Chem. Soc. 2017, 139, 3209. doi:https://doi.org/10.1021/jacs.6b13229
5. T. A. Reekie, C. M. Williams, L. M. Rendina, M. Kassiou, J. Med. Chem. 2019, 62, 1078. doi:https://doi.org/10.1021/acs.jmedchem.8b00888
6. A. Johansson, et al., J. Med. Chem. 2016, 59, 2497. doi:https://doi.org/10.1021/acs.jmedchem.5b01654

Download TCI brochure Building Blocks for Bioisosteric Replacement in Medicinal Chemistry (PDF)

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Source

• TCI Product Highlights: www.tcichemicals.com/ID/en/product/tci-topics/ProductHighlights_20240624
• TCI product page B5479: tcichemicals.com/ID/en/p/B5479
• TCI product page D5542: tcichemicals.com/ID/en/p/D5542
• TCI product page M3149: tcichemicals.com/ID/en/p/M3149
• TCI product page O0466: tcichemicals.com/ID/en/p/O0466

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