C-Aryl 5a-carba-β-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes

C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.     

Coumarins as novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer

The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors.     

Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia

Thyromimetics that specifically target TRβ have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRβ) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRβ selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.     

Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.     

Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for α-glucosidase

The needs for diverse inhibitors of α-glucosidase (α-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C₁–C₅) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal α-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C₃ with the substituted moiety as 4-(4-aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non-competitive and competitive inhibition modes against yeast and mouse α-Gls, respectively. Furthermore, in the presence of increasing concentration of C₃, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast α-Gls were gradually decreased, suggesting that C₃ binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast α-Gls and C₃ was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of α-Gls.     

The management of diabetes mellitus-imperative role of natural products against dipeptidyl peptidase-4, α-glucosidase and sodium-dependent glucose co-transporter 2 (SGLT2)

Diabetes mellitus is a chronic metabolic disorder which is rapidly spreading worldwide. It is characterized by persistent elevated blood glucose level above normal values (hyperglycemia) due to defect in either insulin secretion or in insulin action or both of them. Currently approved oral synthetic antidiabetic drugs such as biguanides, thiazolidinediones, sulfonylureas, and meglitinides have shown undesirable side effects. Therefore, newer approaches and targets for the management of diabetes mellitus are highly desirable. Dipeptidyl peptidase-4 enzyme, α-glucosidase enzyme and sodium-dependent glucose co-transporter 2 (SGLT2) have been recognized as effective therapeutic targets for the management of diabetes mellitus while natural products are alternatives to oral synthetic hypoglycemic agents. During the last two decades, many researchers were working on the identification and the validation of plant-derived products for curing various diseases. Natural products do not only provide useful drugs in their own right but also provide templates for the development of more effective compounds for enhanced therapeutic potential. Herein, we advocated the vital role of natural products as source of new drugs by presenting promising inhibitors of dipeptidyle peptidase-4 enzyme, α-glucosidase enzyme and (SGLT2) obtained from different medicinal plants as potential candidates for drug development against diabetes mellitus. The structure–activity relationship (SAR) of these various inhibitors is also discussed.     

Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11β-HSD1 in a rat pharmacodynamic model (ED₅₀ = 10 mg/kg).     

Optimization of cyclic sulfamide derivatives as 11β-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11β-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC₅₀ value of 1 nM toward human and mouse 11β-HSD1 and showed good 11β-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11β-HSD1 were suggested.     

Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer’s disease

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC₅₀?=?0.56?μM and 5.12?μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ_1–42 aggregation (IC₅₀?=?3.05?μM) and Cu²⁺-induced Aβ_1–42 aggregation (71.7% at 25.0?μM), and displayed significant disaggregation ability to self- and Cu²⁺-induced Aβ_1–42 aggregation fibrils (75.2% and 77.2% at 25.0?μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.     

Discovery of novel dual functional agent as PPARγ agonist and 11β-HSD1 inhibitor for the treatment of diabetes

PPARγ and 11β-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARγ agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11β-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of α-aryloxy-α-methylhydrocinnamic acids as dual functional agents which activate PPARγ and inhibit 11β-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARγ (EC₅₀ = 6.76 μM) and 11β-HSD1 (IC₅₀ = 0.76 μM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.     

Synthesis of 3-spiromorpholinone androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3

Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors. The target compounds exhibited strong inhibition of 17β-HSD3 in rat testis homogenate (87–92% inhibition at 1 μM).     

Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-secretase (BACE1)

The inhibition of β secretase (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). A novel series of 4-bromophenyl piperazine derivatives coupled to the phenylimino-2H-chromen-3-carboxamide scaffold were investigated as BACE1 inhibitors in this study. Docking study suggested that the phenyl-imino group of the scaffold establishes favorable π–π stacking interaction with side chain of Phe108 of flap pocket. Some of the docking proposed derivatives were synthesized and evaluated for BACE1 inhibitory activity using a FRET-based assay. High BACE1 inhibitory activities were observed from derivatives containing fused heteroaromtic groups attached through the aliphatic linkage to the N4-piperazine moiety, which may be attributed to the engagement of effective interactions with S1–S′1 sub-pocket residues. Of the most potent compounds, 9e displayed an IC₅₀ value for BACE1 of 98 nM. Some of these derivatives demonstrated good inhibitory activity on Aβ production in N2a-APPswe cells at 5 and 10 μM. These compounds might be considered as promising BACE1 inhibitory agents that could lower Aβ production in AD.     

Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors

A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).     

Development of 3-substituted-androsterone derivatives as potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3

17Beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Δ?-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3β-substituted-androsterone derivatives and we tested their inhibitory activity on 17β-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17β-HSD3 overexpressed in HEK-293 cells (homogenized cells). The most active compound when tested in intact HEK-293 transfected cells, namely (3α,5α)-3-{[trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl] sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one (15b), shows an IC?? value of 6 nM, this compound is thus eight times more active than our reference compound D-5-2 (IC??=51 nM). This new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile. Compound 15b is thus a good candidate for further in vivo studies on rodents.     

Design,synthesis and evaluation of pyrazolopyrimidinone derivatives as novel PDE9A inhibitors for treatment of Alzheimer’s disease

Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer’s disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC₅₀ of 2.0 nM against PDE9, showed good metabolic stability (t_1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.     

AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes

G-protein-coupled receptor (GPR) 119 is involved in glucose-stimulated insulin secretion (GSIS) and represents a promising target for the treatment of type 2 diabetes as it is highly expressed in pancreatic β-cells. Although a number of oral GPR119 agonists have been developed, their inability to adequately directly preserve β-cell function limits their effectiveness. Here, we evaluated the therapeutic potential of a novel small-molecule GPR119 agonist, AS1907417, which represents a modified form of a 2,4,6-tri-substituted pyrimidine core agonist, AS1269574, we previously identified. The exposure of HEK293 cells expressing human GPR119, NIT-1 cells expressing human insulin promoter, and the pancreatic β-cell line MIN-6-B1 to AS1907417, enhanced intracellular cAMP, GSIS, and human insulin promoter activity, respectively. In in vivo experiments involving fasted normal mice, a single dose of AS1907417 improved glucose tolerance, but did not affect plasma glucose or insulin levels. Twice-daily doses of AS1907417 for 4 weeks in diabetic db/db, aged db/db mice, ob/ob mice, and Zucker diabetic fatty rats reduced hemoglobin A1c levels by 1.6%, 0.8%, 1.5%, and 0.9%, respectively. In db/db mice, AS1907417 improved plasma glucose, plasma insulin, pancreatic insulin content, lipid profiles, and increased pancreatic insulin and pancreatic and duodenal homeobox 1 (PDX-1) mRNA levels. These data demonstrate that novel GPR119 agonist AS1907417 not only effectively controls glucose levels, but also preserves pancreatic β-cell function. We therefore propose that AS1907417 represents a new type of antihyperglycemic agent with promising potential for the effective treatment of type 2 diabetes.     

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer’s disease

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.     

Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO₂) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.     

Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics

The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC(50) = 36nM, EC(50) = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.     

Structure-aided optimization of 3-O-β-chacotriosyl epiursolic acid derivatives as novel H5N1 virus entry inhibitors

It is urgent to develop new antiviral agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain pentacyclic triterpene saponins with 3-O-β-chacotriosyl residue are novel H5N1 virus entry inhibitors. In the present study, a series of C-28 modified 3-O-β-chacotriosyl epiursolic acid derivatives via conjugation with different kinds of sides were synthesized, of which anti-H5N1 activities in A549 cells were evaluated in vitro. Among them, 10 exhibited strongest anti-H5N1 potency at the low-micromole level without cytotoxicity, surpassing the potency of ribavirin. Further mechanism studies of the lead compound 10 based on HI, SPR and molecular modeling revealed that these new 3-epiursolic acid saponins could bind tightly to the viral envelope HA protein, thus blocking the invasion of H5N1 viruses into host cells.