Jitendra Sattigeri

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.

Discovery of conformationally rigid 3-azabicyclo[3.1.0]hexane-derived dipeptidyl peptidase-IV inhibitors

The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.

Pharmacodynamic and pharmacokinetic profile of RBx 343E48F0: A novel, long acting muscarinic receptor antagonist

RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.

Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome

Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.

Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model.

Aim: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent. Material and Methods: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats. Results: RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900–9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P < 0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats. Conclusions: The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.

Design, synthesis and biological evaluation of spiropyrimidinetriones oxazolidinone derivatives as antibacterial agents

Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome.

Synthesis and evaluation of thiomannosides, potent and orally active FimH inhibitors

FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.