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Volume 18
Issue 6
10.3390/ph18060814
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach

by
Srinivasulu Cherukupalli
1,
Carsten Degenhart
2,
Peter Habenberger
2,
Anke Unger
2,
Jan Eickhoff
2,
Bård Helge Hoff
1,* and
Eirik Sundby
3,*
1
Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491 Trondheim, Norway
2
Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227 Dortmund, Germany
3
Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(6), 814; https://doi.org/10.3390/ph18060814
Submission received: 29 April 2025 / Revised: 22 May 2025 / Accepted: 23 May 2025 / Published: 28 May 2025
(This article belongs to the Special Issue Design and Synthesis of Small Molecule Kinase Inhibitors)
Versions Notes

Abstract

Background/Objectives: Colony stimulating factor 1 receptor kinase (CSF1R) is a well-validated molecular target in drug discovery for various reasons. Based on the structure of an early lead molecule identified in our lab and the marketed drug Pexidartinib (PLX3397), we merged fragments of Pexidartinib with our pyrrolo[2,3-d]pyrimidine nucleus, and the idea was supported by initial molecular docking studies. Thus, several new compounds were synthesized with Pexidartinib fragments on C4, C5, and C6 on the pyrrolopyrimidine scaffold using molecular hybridization. Methods: Nine final products were synthesized using a combination of Buchwald-Hartwig and Suzuki-Miyaura cross-coupling reactions in three to four steps and in good yields. The analogues were subsequently profiled as CSF1R inhibitors in enzymatic and cellular assays, and ADME properties were evaluated for some derivatives. Results: N-Methyl-N-(3-methylbenzyl)-6-(6-((pyridin-3-ylmethyl)amino)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (12b) emerged as the most potent CSF1R inhibitor, showing low-nanomolar enzymatic activity, cellular efficacy, and favorable ADME properties, highlighting its promise as a lead compound for further development. Conclusions: These findings suggest that combining structural elements from previously reported CSF1R inhibitors such as Pexidartinib could guide the development of improved drug candidates targeting this kinase.
Keywords: CSF1R inhibitors; pyridine; pyrrolo[2,3-d]pyrimidine; scaffold hopping; molecular hybridization; Pexidartinib CSF1R inhibitors; pyridine; pyrrolo[2,3-d]pyrimidine; scaffold hopping; molecular hybridization; Pexidartinib

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MDPI and ACS Style

Cherukupalli, S.; Degenhart, C.; Habenberger, P.; Unger, A.; Eickhoff, J.; Hoff, B.H.; Sundby, E. Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach. Pharmaceuticals 2025, 18, 814. https://doi.org/10.3390/ph18060814

AMA Style

Cherukupalli S, Degenhart C, Habenberger P, Unger A, Eickhoff J, Hoff BH, Sundby E. Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach. Pharmaceuticals. 2025; 18(6):814. https://doi.org/10.3390/ph18060814

Chicago/Turabian Style

Cherukupalli, Srinivasulu, Carsten Degenhart, Peter Habenberger, Anke Unger, Jan Eickhoff, Bård Helge Hoff, and Eirik Sundby. 2025. "Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach" Pharmaceuticals 18, no. 6: 814. https://doi.org/10.3390/ph18060814

APA Style

Cherukupalli, S., Degenhart, C., Habenberger, P., Unger, A., Eickhoff, J., Hoff, B. H., & Sundby, E. (2025). Design and Synthesis of Pyridine-Based Pyrrolo[2,3-d]pyrimidine Analogs as CSF1R Inhibitors: Molecular Hybridization and Scaffold Hopping Approach. Pharmaceuticals, 18(6), 814. https://doi.org/10.3390/ph18060814

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