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Inhibition of Insul...
Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
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- Engen, Karin (författare)
- Uppsala universitet,Institutionen för läkemedelskemi,Preparative Medicinal Chemistry
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Lundbäck, Thomas (författare)
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- Yadav, Anubha (författare)
- Uppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Puthiyaparambath, Sharathna (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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- Rosenström, Ulrika (författare)
- Uppsala universitet,Preparativ läkemedelskemi
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- Gising, Johan, 1981- (författare)
- Uppsala universitet,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab
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Jenmalm Jensen, Annika (författare)
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- Hallberg, Mathias, 1971- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Larhed, Mats (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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(creator_code:org_t)
- MDPI, 2024
- 2024
- Engelska.
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067.
- Relaterad länk:
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https://doi.org/10.3...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Inhibition of Insulin-regulated Aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign identifying novel small-molecule based compounds acting as inhibitors of the enzymatic activity IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 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 pIC50 values of 6.0. 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 Zn2+ 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- Insulin-regulated aminopeptidase
- IRAP
- inhibitors
- Medicinal Chemistry
- Läkemedelskemi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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