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Disulfide cyclized ...
Disulfide cyclized tripeptide analogues of angiotensin IV as potent and selective inhibitors of insulin-regulated aminopeptidase (IRAP)
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- Andersson, Hanna, 1979- (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Demaegdt, Heidi (author)
- Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel
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- Vauquelin, Georges (author)
- Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel
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- Lindeberg, Gunnar (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Karlén, Anders (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Hallberg, Mathias (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Erdélyi, Máté (author)
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- Hallberg, Anders (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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(creator_code:org_t)
- 2010-11-03
- 2010
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:22, s. 8059-8071
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and seems to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. The best inhibitors in the series, compound 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 nM and 5.2 nM, respectively.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- angiotensin IV
- insulin-regulated aminopeptidase
- inhibitor
- disulfide
- NAMFIS
- Pharmaceutical chemistry
- Läkemedelskemi
- Medicinal Chemistry
- Läkemedelskemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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