RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes.
Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.
Singh
Shuchita
S
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana-122001, India.
Roy
Subhasis
S
Sethi
Sachin
S
Benjamin
Biju
B
Sundaram
Sindhuja
S
Khanna
Vivek
V
Kandalkar
Sachin R
SR
Pal
Chanchal
C
Kant
Rajiv
R
Patra
Ashok Kumar
AK
Rayasam
Geetavani
G
Mittra
Shivani
S
Saini
Kulvinder Singh
KS
Paliwal
Jyoti
J
Chugh
Anita
A
Ahmed
Shahadat
S
Sattigeri
Jitendra
J
Cliff
Ian
I
Ray
Abhijit
A
Bansal
Vinay S
VS
Bhatnagar
Pradip Kumar
PK
Davis
Joseph Alex
JA
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D018819:Dipeptidyl Peptidase 4