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Discovery of an Ora...
Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool
- Artikel/kapitelEngelska2020
Förlag, utgivningsår, omfång ...
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2020-07-02
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John Wiley and Sons Ltd,2020
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:kth-286487
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-286487URI
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https://doi.org/10.1002/cmdc.202000175DOI
Kompletterande språkuppgifter
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Språk:engelska
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Sammanfattning på:engelska
Ingår i deldatabas
Klassifikation
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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QC 20201217
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Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.
Ämnesord och genrebeteckningar
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NATURVETENSKAP Kemi Organisk kemi hsv//swe
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NATURAL SCIENCES Chemical Sciences Organic Chemistry hsv//eng
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biostability
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DPP-IV
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in silico testing
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inhibitors
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metabolism
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2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (1h pyrazol 4 yl)thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 3 yl)thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 4 yl)thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 [3 (trifluoromethyl)phenyl]thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 4 oxo 7 (pyridin 3 yl)thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 (2 methoxypyridin 4 yl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 (2 methylpyridin 4 yl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 (3 fluorophenyl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 (3
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5 dimethylisoxazol 4 yl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 (4 fluorophenyl) 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 bromo 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 6 [3 (methylsulfonyl)phenyl] 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 7 bromo 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 7 fluoro 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxo 6 (pyridin 3 yl)thieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxothieno[3
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2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile
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antidiabetic agent
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cytochrome P450
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dipeptidyl peptidase IV inhibitor
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long acting drug
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pyrimidine derivative
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trelagliptin
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unclassified drug
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xanthine derivative
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animal experiment
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area under the curve
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Article
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computer model
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controlled study
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drug bioavailability
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drug design
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drug efficacy
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drug half life
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drug potency
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drug transformation
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glycemic control
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IC50
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in vitro study
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in vivo study
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infant
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male
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maximum plasma concentration
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mean residence time
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metabolic stability
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nonhuman
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priority journal
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rat
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time to maximum plasma concentration
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Dou, W.
(författare)
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Li, M.
(författare)
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Zhou, Yang,1989-KTH,Teoretisk kemi och biologi(Swepub:kth)u1qoay2o
(författare)
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Guo, J.
(författare)
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Zhao, N.
(författare)
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Huang, H.
(författare)
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Zhou, Q.
(författare)
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Hu, W.
(författare)
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Ma, Y.
(författare)
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Zhao, X.
(författare)
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Xie, H.
(författare)
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KTHTeoretisk kemi och biologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:ChemMedChem: John Wiley and Sons Ltd15:16, s. 1608-16171860-71791860-7187
Internetlänk
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Zeng, S.
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Dou, W.
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Li, M.
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Zhou, Yang, 1989 ...
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Guo, J.
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Zhao, N.
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visa fler...
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Huang, H.
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Zhou, Q.
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Hu, W.
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Ma, Y.
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Zhao, X.
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Xie, H.
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visa färre...
- Om ämnet
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NATURVETENSKAP
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och Organisk kemi
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ChemMedChem
- Av lärosätet
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Kungliga Tekniska Högskolan