Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool

• 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

NATURVETENSKAP  -- Kemi -- Organisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Organic Chemistry (hsv//eng)

Nyckelord

biostability

DPP-IV

in silico testing

inhibitors

metabolism

2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (1h pyrazol 4 yl)thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 3 yl)thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 (pyridin 4 yl)thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 4 oxo 6 [3 (trifluoromethyl)phenyl]thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 4 oxo 7 (pyridin 3 yl)thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 (2 methoxypyridin 4 yl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 (2 methylpyridin 4 yl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 (3 fluorophenyl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 (3

5 dimethylisoxazol 4 yl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 (4 fluorophenyl) 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 bromo 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 6 [3 (methylsulfonyl)phenyl] 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 7 bromo 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 7 fluoro 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxo 6 (pyridin 3 yl)thieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

2 [[2 (3 aminopiperidin 1 yl) 7 methyl 4 oxothieno[3

2 d]pyrimidin 3(4h) yl]methyl] 4 fluorobenzonitrile

antidiabetic agent

cytochrome P450

dipeptidyl peptidase IV inhibitor

long acting drug

pyrimidine derivative

trelagliptin

unclassified drug

xanthine derivative

animal experiment

area under the curve

Article

computer model

controlled study

drug bioavailability

drug design

drug efficacy

drug half life

drug potency

drug transformation

glycemic control

IC50

in vitro study

in vivo study

infant

male

maximum plasma concentration

mean residence time

metabolic stability

nonhuman

priority journal

rat

time to maximum plasma concentration

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