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Peer-reviewedCC BY 4.0ACS Central Science

Tetrahydro-Dewar Pyridines (THDPs): Conformationally Programmable Piperidine Isosteres

  • Jan Petrovčič1,2
  • Yaroslav D. Boyko3
  • Tsukasa Tawatari4,5
  • Alexander S. Shved6,2
  • Filippo Preti7,8
  • Marco Fattalini7,8
  • Sergio Rossi7,8
  • Giovanni Lenardon1,5,2
  • Christophe Salomé9
  • Quentin Lefebvre9
  • Thomas C. Fessard9
  • David Šarlah4,6,1
9 affiliations
  1. 1University of Pavia , , V. Torquato Taramelli 12 , ,
  2. 2University of Pavia
  3. 3Merck & Co. Inc
  4. 4Rice University , , , ,
  5. 5University of Illinois Urbana-Champaign
  6. 6University of Illinois , , , ,
  7. 7University of Milano , , V. Golgi 19 , ,
  8. 8SpiroChem AG
  9. 9SpiroChem AG , Mattenstrasse 22 , ,
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Abstract

Bioisosteric replacement is an indispensable tool in a medicinal chemist’s arsenal to strike a fine balance in multiparameter optimization campaigns and to deliver the best molecules for further preclinical development. The piperidine heterocycle is a valuable motif but often requires bioisosteric replacement to improve its ADME (absorption, distribution, metabolism, excretion) profile. Despite recent advances in the field, practitioners still rely on the limited pool of commercially available piperidine isosteres that often have imperfect geometrical overlay. Herein, we explore tetrahydro-Dewar pyridines (THDPs) as rigid, programmable isosteres of piperidines. These building blocks are readily accessible from dihydro-Dewar pyridines (DHDPs), which can be synthesized from pyridine in only two steps using batch or flow photochemistry. Developed synthetic routes provide access to new building blocks and bifunctional linkers suitable for incorporation into various structural contexts. By applying the THDP scaffold to three distinct classes of kinase inhibitors, we demonstrate that THDPs offer a robust solution for testing advanced SAR hypotheses by stabilizing exit vectors while preserving physicochemical properties.

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Cite

BibTeXRIS
BibTeX
@article{petrovcic2026tetrahydrodewar,
  title = {{Tetrahydro-Dewar Pyridines (THDPs): Conformationally Programmable Piperidine Isosteres}},
  author = {Jan Petrovčič and Yaroslav D. Boyko and Tsukasa Tawatari and Alexander S. Shved and Filippo Preti and Marco Fattalini and Sergio Rossi and Giovanni Lenardon and Christophe Salomé and Quentin Lefebvre and Thomas C. Fessard and David Šarlah},
  journal = {ACS Central Science},
  year = {2026},
  month = oct,
  doi = {10.1021/acscentsci.6c01143},
  url = {https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01143/5458479/Tetrahydro-Dewar-Pyridines-THDPs-Conformationally},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tetrahydro-Dewar Pyridines (THDPs): Conformationally Programmable Piperidine Isosteres
AU  - Jan Petrovčič
AU  - Yaroslav D. Boyko
AU  - Tsukasa Tawatari
AU  - Alexander S. Shved
AU  - Filippo Preti
AU  - Marco Fattalini
AU  - Sergio Rossi
AU  - Giovanni Lenardon
AU  - Christophe Salomé
AU  - Quentin Lefebvre
AU  - Thomas C. Fessard
AU  - David Šarlah
PY  - 2026
DA  - 2026/10/26
JO  - ACS Central Science
DO  - 10.1021/acscentsci.6c01143
UR  - https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01143/5458479/Tetrahydro-Dewar-Pyridines-THDPs-Conformationally
AB  - Bioisosteric replacement is an indispensable tool in a medicinal chemist’s arsenal to strike a fine balance in multiparameter optimization campaigns and to deliver the best molecules for further preclinical development. The piperidine heterocycle is a valuable motif but often requires bioisosteric replacement to improve its ADME (absorption, distribution, metabolism, excretion) profile. Despite recent advances in the field, practitioners still rely on the limited pool of commercially available piperidine isosteres that often have imperfect geometrical overlay. Herein, we explore tetrahydro-Dewar pyridines (THDPs) as rigid, programmable isosteres of piperidines. These building blocks are readily accessible from dihydro-Dewar pyridines (DHDPs), which can be synthesized from pyridine in only two steps using batch or flow photochemistry. Developed synthetic routes provide access to new building blocks and bifunctional linkers suitable for incorporation into various structural contexts. By applying the THDP scaffold to three distinct classes of kinase inhibitors, we demonstrate that THDPs offer a robust solution for testing advanced SAR hypotheses by stabilizing exit vectors while preserving physicochemical properties.
SN  - 2374-7943
SN  - 2374-7951
ER  -