Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

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Maslov, Ivan O.Lomonosov Moscow State Univ, Fac Biol, Dept Bioorgan Chem, Moscow 119991, Russia. (author)

Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4)

Article/chapterEnglish2022

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2022-02-22
MDPI AG,2022
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-472930
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-472930URI
https://doi.org/10.3390/ph15030273DOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:art swepub-publicationtype

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Compounds that contain (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid substituted with bicyclic amino moiety (2-aza-bicyclo[2.2.1]heptane) were designed using molecular modelling methods, synthesised, and found to be potent DPP-4 (dipeptidyl peptidase-4) inhibitors. Compound 12a (IC50 = 16.8 +/- 2.2 nM), named neogliptin, is a more potent DPP-4 inhibitor than vildagliptin and sitagliptin. Neogliptin interacts with key DPP-4 residues in the active site and has pharmacophore parameters similar to vildagliptin and sitagliptin. It was found to have a low cardiotoxic effect compared to sitagliptin, and it is superior to vildagliptin in terms of ADME properties. Moreover, compound 12a is stable in aqueous solutions due to its low intramolecular cyclisation potential. These findings suggest that compound 12a has unique properties and can act as a template for further type 2 diabetes mellitus drug development.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
type 2 diabetes mellitus
DPP-4 inhibitors
molecular docking
structure-activity relationship
stereoisomerism
rotameric forms

Added entries (persons, corporate bodies, meetings, titles ...)

Zinevich, Tatiana, VLomonosov Moscow State Univ, Fac Biol, Dept Bioorgan Chem, Moscow 119991, Russia. (author)
Kirichenko, Olga G.LLC Inst Mitoengn MSU, Moscow 119899, Russia. (author)
Trukhan, Mikhail, VIM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia. (author)
Shorshnev, Sergey, VChembridge Corp, Moscow 119435, Russia. (author)
Tuaeva, Natalya O.IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia.;Serbsky Inst Gen & Forens Psychiat, Moscow 119839, Russia. (author)
Gureev, Maxim A.IM Sechenov First Moscow State Med Univ, World Class Res Ctr Digital Biodesign & Personali, Moscow 119991, Russia.;Sirius Univ Sci & Technol, Dept Computat Biol, Olymp Ave 1, Soci 354340, Russia. (author)
Dahlén, AmeliaUppsala universitet,Institutionen för kirurgiska vetenskaper,Funktionell farmakologi och neurovetenskap(Swepub:uu)ameda251 (author)
Porozov, Yuri B.IM Sechenov First Moscow State Med Univ, World Class Res Ctr Digital Biodesign & Personali, Moscow 119991, Russia.;Sirius Univ Sci & Technol, Dept Computat Biol, Olymp Ave 1, Soci 354340, Russia. (author)
Schiöth, Helgi B.Uppsala universitet,Institutionen för kirurgiska vetenskaper,IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia.,Funktionell farmakologi och neurovetenskap(Swepub:uu)helgschi (author)
Trukhan, Vladimir M.IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia. (author)
Lomonosov Moscow State Univ, Fac Biol, Dept Bioorgan Chem, Moscow 119991, Russia.LLC Inst Mitoengn MSU, Moscow 119899, Russia. (creator_code:org_t)

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In:Pharmaceuticals: MDPI AG15:31424-8247

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By the author/editor: Maslov, Ivan O.; Zinevich, Tatian ...; Kirichenko, Olga ...; Trukhan, Mikhail ...; Shorshnev, Serge ...; Tuaeva, Natalya ...; show more...; Gureev, Maxim A.; Dahlén, Amelia; Porozov, Yuri B.; Schiöth, Helgi B ...; Trukhan, Vladimi ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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