Pradip Jadav

Discovery of potent, selective and orally bioavailable triaryl-sulfonamide based PTP1B inhibitors

A novel series of pTyr mimetics containing triaryl-sulfonamide derivatives (5a-r) are reported as potent and selective PTP1B inhibitors. Some of the test compounds (5o and 5p) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro). The lead compound 5o showed potent antidiabetic activity (in vivo), along with improved pharmacokinetic profile. These preliminary results confirm discovery of highly potent and selective PTP1B inhibitors for the treatment of T2DM.

Discovery of Orally Active, Potent, and Selective Benzotriazole-Based PTP1B Inhibitors**

The worldwide incidence of metabolic syndromes such as obesity and diabetes are increasing at an alarming rate. Patients that suffer from obesity-induced type 2 diabetes (informally known as diabesity) are at increased risk of cardiovascular disease; their numbers pose a significant economic burden on health services. Type 2 diabetes mellitus (T2DM) is clinically characterized by increased blood glucose levels, either due to defects in insulin secretion, insulin resistance, or both. Current treatments for diabetic patients include various oral antihyperglycemic agents; however, over a period of time nearly half of T2DM sufferers lose their response to these agents and thereby require insulin therapy. Except incretin therapies, most of the available anti-hyperglycemic agents including insulin promote weight gain, which further aggravates obesity-associated cardiovascular risk and insulin resistance. Thus, there is an urgent need to develop novel agents for glycemic control that can complement existing therapies and prevent the progression of secondary complications associated with diabesity. In recent years, development of protein tyrosine phosphatase 1B (PTP1B) inhibitors has been considered as one of the best validated biological targets for the treatment of T2DM. PTP1B acts as a negative regulator in insulin signaling pathways; it dephosphorylates key tyrosine residues within the regulatory domain of the b-subunit of the insulin receptor. Thus, the inhibition of PTP1B activity has the potential for enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. Gene knockout studies in animals have also demonstrated that PTP1B / mice show increased insulin sensitivity and are resistant to diet-induced obesity. Over the past two decades, several structurally diverse small-molecule-based PTP1B inhibitors have been developed, including Ertiprotafib, which was discontinued in phase II clinical trials owing to lack of efficacy and dose-dependent side effects. Most of the initial PTP1B inhibitors, such as phosphonates, carboxylic acids, and difluoromethylphosphonates (DFMPs), were designed to bind to the active site (site 1/A) by mimicking the phosphotyrosine (pTyr) substrate. However, achieving PTP1B selectivity over closely associated PTPs (PTPa, LAR, CD45, VHR, SHP-1, SHP-2, and T-cell protein tyrosine phosphatase (TCPTP)) is one of the major challenges, as most of the closely associated PTPs, particularly TCPTP, share a high degree of primary sequence identity (92%) in the active site (pTyr binding pocket). Lack of oral bioavailability is another important issue in the development of potent and selective PTP1B inhibitors, as the majority of the active-site-directed PTP1B inhibitors exhibit limited cell permeability due to the presence of negatively charged polar groups. To address this problem, Zhang and colleagues identified an additional noncatalytic aryl phosphate binding site (site 2/B) proximal to the catalytic phosphate binding site. Site B of PTP1B differs from that of TCPTP by a few amino acids (F52Y and A27S) and thus offers an opportunity to improve selectivity over TCPTP. Consequently, dual-site inhibitors were designed to bind across both sites A and B, to achieve additive effects and thereby improve potency and selectivity toward PTP1B over closely associated PTPs. Based on this dual binding site concept, various DFMP-based PTP1B inhibitors such as arylketone 1, benzotriazoles 2a and 2b, and naphthyl derivative 3 were developed (Figure 1). The X-ray crystal structure of PTP1B in complex with compound 2b reveals that sites A and B each have a DFMP moiety anchored into it. The benzotriazole ring system also functions as an anchor and is located under the YRD loop, thereby rigidly locking the molecule into the active site and providing good selectivity for PTP1B over other PTPs. The fourth substituent (benzene ring) occupies a hydrophobic pocket. Altogether, this signifies that the presence of all four substituents oriented rigidly by the molecule’s stereocenter is essential for high potency and selectivity. Although results of oral bioavailability and in vivo antidiabetic activity assays for compound 2a have yet to be published, in vitro results show improved PTP1B inhibitory activity (IC50= 5 nm) and moderate selectivity (sevenfold) over TCPTP (IC50= 36 nm). The X-ray crystal structure of PTP1B in complex with compound 2a illustrates that a methoxy group aligns very closely (3.7 ) to the side chain of F52 (site B). Oral administration of compounds 1 and 3 demonstrated good antidiabetic activity (compound 3 : ED50=0.8 mgkg , p.o.) and oral bioavailability (compounds 1 and 3: F=13 and 24%, respectively) in different animal species, despite their moderate in vitro PTP1B inhibitory activity (IC50=120 nm) and poor selectivity [a] D. Patel, Dr. M. Jain, Dr. R. Bahekar, P. Jadav, B. Darji, Y. Siriki, Dr. D. Bandyopadhyay, Dr. A. Joharapurkar, S. Kshirsagar, H. Patel, M. Shaikh, Dr. K. V. V. M. Sairam, P. Patel Department of Medicinal Chemistry, New Drug Discovery Division Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad 382210 (India) Fax: (+91)2717-665-355 E-mail : rajeshbahekar@zyduscadila.com [b] D. Patel, Prof. S. R. Shah Department of Chemistry, Faculty of Science M.S. University of Baroda, Vadodara 390002 (India) Fax: (+91)0265-79-3693 E-mail : Shailesh-chem@msubaroda.ac.in [**] ZRC communication No. 378 (part of PhD thesis work of D.P.) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201100077.

Long-acting peptidomimetics based DPP-IV inhibitors

Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.

Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors

A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.

Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor.

Dipeptidyl peptidase‐4 (DPP‐4) is responsible for degradation of glucagon‐like peptide 1 (GLP‐1) and gastric inhibitory polypeptide (GIP), the endogenous incretins that stimulate glucose‐dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP‐4 inhibitor ZYDPLA1.

Discovery of liver selective non-steroidal glucocorticoid receptor antagonist as novel antidiabetic agents

Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a-q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.

ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase‐4, for the treatment of Type 2 diabetes mellitus

Dipeptidyl peptidase (DPP)‐4 inhibitors increase levels of glucagon‐like peptide‐1 (GLP‐1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP‐4 inhibitor, ZY15557, that has a sustained action and long half‐life.

ZY15557, a novel, long acting DPP‐4 inhibitor for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase (DPP)‐4 inhibitors increase levels of glucagon‐like peptide‐1 (GLP‐1) and provide clinical benefit in the treatment of type 2 diabetes mellitus. As longer acting inhibitors have therapeutic advantages, we developed a novel DPP‐4 inhibitor, ZY15557, that has a sustained action and long half‐life.

Peptidomimetics as potent and selective PTP1B inhibitors.

A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors.