Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation
Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/5/2516 |
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| author | Karin Engen Thomas Lundbäck Anubha Yadav Sharathna Puthiyaparambath Ulrika Rosenström Johan Gising Annika Jenmalm-Jensen Mathias Hallberg Mats Larhed |
| author_facet | Karin Engen Thomas Lundbäck Anubha Yadav Sharathna Puthiyaparambath Ulrika Rosenström Johan Gising Annika Jenmalm-Jensen Mathias Hallberg Mats Larhed |
| author_sort | Karin Engen |
| collection | DOAJ |
| description | Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC<sub>50</sub> value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound’s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn<sup>2+</sup> ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding. |
| first_indexed | 2024-04-25T00:29:27Z |
| format | Article |
| id | doaj.art-d6b2ff98e8d64d86a861f85162eae0be |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:29:27Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d6b2ff98e8d64d86a861f85162eae0be2024-03-12T16:45:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01255251610.3390/ijms25052516Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and EvaluationKarin Engen0Thomas Lundbäck1Anubha Yadav2Sharathna Puthiyaparambath3Ulrika Rosenström4Johan Gising5Annika Jenmalm-Jensen6Mathias Hallberg7Mats Larhed8Department of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenChemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Division of Chemical Biology and Genome Engineering, Karolinska Institutet, Tomtebodavägen 23A, SE-171 65 Solna, SwedenThe Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenThe Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenThe Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenChemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Division of Chemical Biology and Genome Engineering, Karolinska Institutet, Tomtebodavägen 23A, SE-171 65 Solna, SwedenThe Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, Uppsala University, BMC, P.O. Box 591, SE-751 24 Uppsala, SwedenThe Beijer Laboratory, Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, P.O. Box 574, SE-751 23 Uppsala, SwedenInhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC<sub>50</sub> value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound’s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn<sup>2+</sup> ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.https://www.mdpi.com/1422-0067/25/5/2516IRAPimidazo [1,5-α]pyridine-based inhibitorsenzyme inhibitorinsulin-regulated aminopeptidase |
| spellingShingle | Karin Engen Thomas Lundbäck Anubha Yadav Sharathna Puthiyaparambath Ulrika Rosenström Johan Gising Annika Jenmalm-Jensen Mathias Hallberg Mats Larhed Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation International Journal of Molecular Sciences IRAP imidazo [1,5-α]pyridine-based inhibitors enzyme inhibitor insulin-regulated aminopeptidase |
| title | Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation |
| title_full | Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation |
| title_fullStr | Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation |
| title_full_unstemmed | Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation |
| title_short | Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation |
| title_sort | inhibition of insulin regulated aminopeptidase by imidazo 1 5 α pyridines synthesis and evaluation |
| topic | IRAP imidazo [1,5-α]pyridine-based inhibitors enzyme inhibitor insulin-regulated aminopeptidase |
| url | https://www.mdpi.com/1422-0067/25/5/2516 |
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