TY - JOUR

T1 - Dual PTP1B/TC-PTP Inhibitors: Biological Evaluation of 3-(Hydroxymethyl)cinnoline-4(1H)-Ones

AU - Derkach, Kira V.

AU - Gureev, Maxim A.

AU - Babushkina, Anastasia A.

AU - Mikhaylov, Vladimir N.

AU - Zakharova, Irina O.

AU - Bakhtyukov, Andrey A.

AU - Sorokoumov, Viktor N.

AU - Novikov, Alexander S.

AU - Krasavin, Mikhail

AU - Shpakov, Alexander O.

AU - Balova, Irina A.

PY - 2023/2/24

Y1 - 2023/2/24

N2 - Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats. Likewise, the effects of the compounds on glucose tolerance, insulin resistance, as well as insulin and leptin levels, have been evaluated. In addition, the effects on PTP1B, TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the insulin and leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in body weight and food intake, improved glucose tolerance, attenuated hyperinsulinemia, hyperleptinemia and insulin resistance, and also compensatory increased expression of the PTP1B and TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4( 1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4( 1H)-one (compound 4) with mixed PTP1B/TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/TC-PTP dual inhibition, and on the promise of using mixed PTP1B/TC-PTP inhibitors to correct metabolic disorders.

AB - Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats. Likewise, the effects of the compounds on glucose tolerance, insulin resistance, as well as insulin and leptin levels, have been evaluated. In addition, the effects on PTP1B, TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the insulin and leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in body weight and food intake, improved glucose tolerance, attenuated hyperinsulinemia, hyperleptinemia and insulin resistance, and also compensatory increased expression of the PTP1B and TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4( 1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4( 1H)-one (compound 4) with mixed PTP1B/TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/TC-PTP dual inhibition, and on the promise of using mixed PTP1B/TC-PTP inhibitors to correct metabolic disorders.

KW - Animals

KW - Enzyme Inhibitors/pharmacology

KW - Glucose

KW - Insulin Resistance

KW - Insulin/metabolism

KW - Male

KW - Obesity/metabolism

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism

KW - Rats

KW - Rats, Wistar

KW - T-Lymphocytes/metabolism

KW - phosphatase inhibitors

KW - cinnolines

KW - insulin

KW - tyrosine phosphatase 1B

KW - leptin

KW - T-cell tyrosine phosphatase

KW - obesity

UR - https://www.mendeley.com/catalogue/49cb5aea-e149-3594-aef5-c2e601db731a/

U2 - 10.3390/ijms24054498

DO - 10.3390/ijms24054498

M3 - Article

C2 - 36901928

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 5

M1 - 4498

ER -