PMID- 31685773
OWN - NLM
STAT- MEDLINE
DCOM- 20200505
LR  - 20200707
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 42
IP  - 11
DP  - 2019
TI  - A Novel TNF-alpha Converting Enzyme (TACE) Selective Inhibitor JTP-96193 Prevents 
      Insulin Resistance in KK-A(y) Type 2 Diabetic Mice and Diabetic Peripheral 
      Neuropathy in Type 1 Diabetic Mice.
PG  - 1906-1912
LID - 10.1248/bpb.b19-00526 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) converting enzyme/a disintegrin and 
      metalloproteinase domain-containing protein 17 (TACE/ADAM17) is a key sheddase 
      that releases TNF-alpha from its inactive precursor and is thought as a new drug 
      target to inhibit TNF-alpha production. In the present study, pharmacological effects 
      of a novel TACE selective inhibitor, JTP-96193, on type 2 diabetes and diabetic 
      peripheral neuropathy (DPN) as its major complication was examined. Enzyme 
      inhibitory activity of JTP-96193 on TACE and other ADAMs was measured in in 
      vitro. High fat-induced obese mice and type 2 diabetic KK-A(y) mice were used to 
      evaluate the effect of JTP-96193 on insulin resistance. Finally, streptozotocin 
      (STZ)-induced diabetic mice were treated with JTP-96193 to evaluate the sciatic 
      motor nerve conduction velocities (MNCV). JTP-96193 selectively inhibited human 
      TACE activity with IC(50) value of 5.4 nM and showed more than 1800-fold 
      selectivity against other matrix metalloproteinases. In mouse models of obesity 
      and diabetes, JTP-96193 reduced the TNF-alpha release from the fat tissue and 
      prevented development of diabetes and improved insulin resistance, respectively. 
      Furthermore, JTP-96193 prevented delay of sciatic MNCV without any effects on 
      blood glucose or insulin levels in STZ-induced diabetic mice. TACE inhibitor is 
      effective on insulin resistance and DPN independent from glucose-lowering effect. 
      These pharmacological properties of JTP-96193 may be helpful to treat type 2 
      diabetes accompanied by its microvascular complications.
FAU - Maekawa, Mariko
AU  - Maekawa M
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Tadaki, Hironobu
AU  - Tadaki H
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Tomimoto, Daisuke
AU  - Tomimoto D
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Okuma, Chihiro
AU  - Okuma C
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Sano, Ryuhei
AU  - Sano R
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Ishii, Yukihito
AU  - Ishii Y
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Katsuda, Yoshiaki
AU  - Katsuda Y
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Yoshiuchi, Hiromi
AU  - Yoshiuchi H
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Kakefuda, Reina
AU  - Kakefuda R
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
FAU - Ohta, Takeshi
AU  - Ohta T
AD  - Laboratory of Animal Physiology and Functional Anatomy, Graduate School of 
      Agriculture, Kyoto University.
FAU - Sasase, Tomohiko
AU  - Sasase T
AD  - Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research 
      Institute, Japan Tobacco Inc.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Blood Glucose)
RN  - 0 (JTP-96193)
RN  - 0 (Thiazoles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (Adam17 protein, mouse)
RN  - EC 3.4.24.86 (Adam17 protein, rat)
SB  - IM
MH  - ADAM17 Protein/*antagonists & inhibitors/metabolism
MH  - Adipose Tissue/drug effects/metabolism
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Diabetes Mellitus, Experimental/*drug therapy/metabolism
MH  - Diabetes Mellitus, Type 1/drug therapy/metabolism
MH  - Diabetes Mellitus, Type 2/drug therapy/metabolism
MH  - Diabetic Neuropathies/blood/*drug therapy
MH  - *Insulin Resistance
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred ICR
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Thiazoles/*pharmacology/therapeutic use
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - TNF-alpha converting enzyme (TACE)
OT  - diabetes
OT  - diabetic peripheral neuropathy
OT  - insulin resistance
OT  - tumor necrosis factor-alpha (TNF-alpha)
EDAT- 2019/11/07 06:00
MHDA- 2020/05/06 06:00
CRDT- 2019/11/06 06:00
PHST- 2019/11/06 06:00 [entrez]
PHST- 2019/11/07 06:00 [pubmed]
PHST- 2020/05/06 06:00 [medline]
AID - 10.1248/bpb.b19-00526 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2019;42(11):1906-1912. doi: 10.1248/bpb.b19-00526.