Shailesh R. Shah

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 and synthesis of novel oxazole containing 1,3-Dioxane-2-carboxylic acid derivatives as PPAR α/γ dual agonists

A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR alpha/gamma dual agonists. Structural requirements for PPARalpha/gamma dual agonism of 1,3-dioxane carboxylic acid derivatives included the structural similarity with potent glitazones in fibric acid chemotype. The compounds with this pharmacophore and substituted oxazole as a lipophilic heterocyclic tail were synthesized and evaluated for their in vitro PPAR agonistic potential and in vivo hypoglycemic and hypolipidemic efficacy in animal models. Lead compound 2-methyl-c-5-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy)-benzyl]-1,3-dioxane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats.

Discovery of a highly orally bioavailable c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid as a potent hypoglycemic and hypolipidemic agent ☆

A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARalpha and gamma. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.

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.

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification☆

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.

Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

Modulation of PPAR receptor subtype selectivity of the ligands: aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety.

Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism.

Synthesis and Characterization of Cycloaromatic Polyamines to Cure Epoxy Resin for Industrial Applications

Cycloaromatic polyamines based on aniline, 4,4′-diaminodiphenylmethane and formaldehyde have been synthesized varying the molar ratio of aniline and formaldehyde keeping the amount of 4,4′-diaminodiphenylmethane constant via a single-step process, coded as PO1, PO2 and PO3. The resinous material of polyamines has been employed for curing studies of commercially available epoxy resinsw. The effect of time, temperature and the concentration of polyamines as curing agent have been studied. The epoxy specimens were further used for testing different dielectric properties such as resistivity, dielectric strength, dissipation factor and dielectric constant with an objective of their application as dielectric materials.