Ritesh Agrawal

The first approved agent in the Glitazar's Class: Saroglitazar.

The new chemical entity (NCE) has been knocked as novel antidiabetic agent, e.g. Saroglitazar. Saroglitazar is a drug for the treatment of Type II diabetes. Saroglitazar is marketed under the trade name Lipaglyn, developed by the Zydus Cadila. Lipaglyn is the first indigenously developed NCE by any Indian pharmaceutical company, ever. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in June 2013. Lipaglyn is indicated for the patients suffering from diabetes dyslipidemia. It also provides the option of a once-daily oral therapy. Saroglitazar regulates the lipid parameters as well as glycemic control. The present article describes Saroglitazar with its chemical synthesis and patent status with its summary of clinical studies.

Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma (γ) agonist.

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (γ), which is developed by Dr. Reddys laboratories India. Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. Balaglitazone is currently being evaluated in phase III clinical trial in United States and Europe. Selective PPAR-γ modulators bind in distinct manners to the ligand-binding pocket of PPAR-γ, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved novel antidiabetic agents are in current development. Clinical studies conducted with 409 subjects of randomized, double blind, parallel-group placebo and active comparator-controlled subject groups to determine the efficacy and safety of Balaglitazone. The study showed that the trial met its primary endpoint. Balaglitazone treated groups shown significantly reduce of HbA1c (%), FSG (mmol/L), postprandial glucose as comparison to pioglitazone. Phase III clinical studies data clearly shows that Balaglitazone provides robust glycemic control as an add-on to insulin therapy. Balaglitazone 10 mg and 20 mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45 mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45 mg. Hence, Balaglitazone is prominent candidate of new glitazone which requires fewer doses as comparison pioglitazone and shows better safety profile less incidence of special adverse effect like heart failure, peripheral oedema, and myocardial infarction. Unlike other marketed PPAR gamma agonists, Balaglitazone shows less fluid retention, less heart enlargement and no reduction of bone formation than full PPAR gamma agonists in preclinical studies. In present review, we have tried to cover classification PPARs various ligands, chemistry, physical properties, commercial synthesis, current patent status, polymorphic information, receptor interaction, pharmacophore rational, mechanism, adverse effect and clinical status of Balaglitazone, giving emphasis on medicinal chemistry aspect.

Apixaban: A New Player in the Anticoagulant Class

Apixaban (BMS-562247-01) is a compound being investigated as an anticoagulant. Apixaban molecule is developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban, a coagulation factor Xa inhibitor, approved in the E.U. in 2011 for the prevention of venous thromboembolic events in adult patients, who have undergone elective hip or knee replacement. The Apixaban based drug will be marketed under the brand name Eliquis® and is expected to rack up annual sales of over

Linagliptin: A Novel Methylxanthin Based Approved Dipeptidyl Peptidase-4 Inhibitor

2.5 billion. Apixaban is expected to provide stiff competition to warfarin, a popular blood thinner used in Europe. Warfarin is known to cause some serious side effects in patients. Apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism in patients experiencing atrial fibrillation by more than 50% (from 3.7% per annum with aspirin to 1.6% per annum with apixaban). Apixaban exhibits superiority to enoxaparin in preventing thrombosis in patients undergoing elective hip replacement surgery with similar bleeding rates. Apixaban is a highly selective and potent Factor Xa Inhibitor with Ki=0 8nM to both free as well as prothrombinase bound FXa. In X-ray crystal structure studies indicate that the pyrazole N-2 nitrogen atom interacts with backbone of Gln192 and the carbonyl oxygen of carboxamide interacts with NH of Gly216. The orientation of phenyllactum in the S4 region indiacates an edge to face interaction with Trp215, which is positioned between the Tyr99 and Phe174. In the present review, we have tried to cover comparative study of various FXa-inhibitors and point out apixaban in the various aspect including molecular chemistry, physical properties, commercial synthesis, current patent status, crystalline polymorphic forms, molecular receptor interaction, pharmacophore rational, mechanism of action, clinical studies, preclinical, adverse effect, available formulation, dose regimen and co-therapy, thus giving emphasis on medicinal chemistry aspects.

Ligand-based pharmacophore detection, screening of potential pharmacophore and docking studies, to get effective glycogen synthase kinase inhibitors

Chemically, methylxanthine nucleus based Linagliptin (BI-1356, BI-1356-BS) is a dipeptidyl peptidase-IV inhibitor, which has been developed by Boehringer Ingelheim in association with Lilly for the treatment of Type-II Diabetes. Linagliptin was marketed by Lilly under the trade name Tradjenta and Trajenta. Linagliptin was approved as the once-daily dose by USFDA on 2 May 2011, for the treatment of Type-II Diabetes. Linagliptin 5mg once daily dose was approved based on a clinical trial program, which was conducted on approximately 4,000 adults with Type-II Diabetes. Linagliptin demonstrated statistically significant mean difference in HbA1c from placebo of up to 0.72 percent, when it was used monotherapically. In patients, who were not adequately controlled on metformin or metformin plus sulphonylurea, the addition of Linagliptin resulted in a statistically significant mean difference in HbA1c from placebo of -0.6 percent. Linagliptin was observed to produce significant reduction in fasting plasma glucose (FPG) compared to placebo, when used as a monotherapy in combination with metformin, sulfonylurea and/or pioglitazone. Linagliptin demonstrated significant reduction post-prandial glucose (PPG) levels in two hours as compared with placebo in monotherapy as well as in combination with metformin. In vitro assays also anticipated that Linagliptin is a potent DPPIV inhibitor as well as it exhibits good selectivity for DPP-IV as compared with other DPPs. The in-vivo studies also demonstrated same anticipation with respect to Linagliptin. Consequently, increasing the GLP-1 levels so far improved glucose tolerance in both healthy animals. X-ray crystallography anticipates that Linagliptin complexes with human DPPIV enzyme, e.g. butynyl substituent occupies the S1 hydrophobic pocket of the enzyme; the aminopiperidine substituent in the xanthine scaffold occupies the S2 subsite and its primary amine interacts with the key amino acid residues, which involves in the recognition of peptide substrates. In the present review, we have tried to cover comparative study of DPPIV inhibitors, chemistry, physical properties, commercial synthesis, patent portfolio, crystalline polymorphic forms of Linagliptin and its receptor interaction, Pharmacophore rational, mechanism, clinical studies, preclinical, adverse effect, available formulations, dose regimen, co-therapy of Linagliptin, giving emphasis on the medicinal chemistry aspects.

Thiazolidine: A Potent Candidate for Central Nervous System Diseases

Glycogen synthase kinase has been identified as an emerging target for various diseases, e.g., type-II diabetes, Alzheimer’s disease, inflammation, cancer, and bipolar disorder. We have identified thirty-one advanced clinically effective GSK-3 ligands, which have been used to establish ligand-based three-dimensional pharmacophore to know the essential features of glycogen synthase kinase inhibitors. Pharmacophore model was built based on known glycogen synthase kinase inhibitors using web-based PharmaGist program. Four point’s pharmacophore with hydrogen-bond acceptors, hydrophobic groups, spatial features, and aromatic rings have been considered to develop pharmacophoric features by PharmaGist program. The pharmacophore model having score 28.169, were selected to screen on ZincPharmer database to derive the novel GSK-3 ligands. All identified Zinc ligands have been filtered, based on the Lipinski’s rule‐of‐five and were also subjected to molecular docking studies. In the present research work, we have covered the ligand-based pharmacophore identification and screening of potential pharmacophore on the ZincPharmer database to derive the fifty novel GSK-3 ligands, having potential to inhibit GSK-3 enzyme. Obtained GSK-3 ligands were docked on GSK-3 enzyme, to support enzyme-ligands interaction features. We have also reviewed the obtained GSK-3 ligands in the traditional Maximal Common Substructure approach.

3D QSAR and Docking Studies of Various Amido and Benzyl-substituted 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl Analogs as DPP-IV Inhibitors

Thiazolidines are multifaceted molecules and exhibit varied types of biological activities, and also showed anticonvulsants and antidepressants activity. It is the diversified class of heterocyclic compounds. Thiazolidinediones (TZD) has been shown beneficial action in various CNS diseases. The significant mechanism of TZD-induced neuroprotection useful in prevention of microglial activation and cytokine that is responsible for inflammatory condition and chemokine expression. At the molecular level TZDs were also responsible to prevent the activation of pro-inflammatory transcription factors as well as promoting the anti-oxidant mechanisms in the injured CNS. Important SAR, molecular mechanism and potent biological activities with special references to central nervous system are discussed in this article. Various investigations suggest that this moiety pave the way for design and discovery of new drug candidates.

3D QSAR and docking study of gliptin derivatives as DPP-IV inhibitors.

The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl analogs reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompass molecular interaction study of 3-amino-4-(2- cyanopyrrolidide)pyrrolidinyl analogs on maestro 8.5 workstation. The Phase study module comprises the five points pharmacophore model (AAHPR.617), consisting two hydrogen bond acceptor (A), one Hydrophobic (H), one Positive(P) and one aromatic ring (R) and with discrete geometries as pharmacophoric feature. The developed pharmacophore model was used to derive a predictive atom-based 3D QSAR model. The obtained 3D QSAR model has an excellent correlation coefficient value (r2=0.9926) along with good statistical significance as shown by high Fisher ratio (F=671.7). The model also exhibits good predictive power, which is confirmed by high value of cross validated correlation coefficient (q2 = 0.7311). The QSAR model suggests that hydrophobic and aromatic characters are crucial for the DPP-IV inhibitory activity. The QSAR model also suggests that the inclusion of hydrophobic substituents would enhance the DPP-IV inhibition. In addition to the hydrogen bond acceptor, hydrophobic character, electro withdrawing character positively contributes to the DPP-IV inhibition. This study provides a set of guidelines for designing compounds with better DPP-IV inhibitory potency.

Novel Serine Protease Dipeptidyl Peptidase IV Inhibitor: Alogliptin

The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 46 xanthine derivatives reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompasses molecular interaction of 46 xanthine ligand through maestro 8.5 software. The QSAR study comprises AHHR.7 pharmacophore hypothesis, which elaborates the three points, e.g. one hydrogen bond acceptor (A), two hydrophobic rings (H) and one aromatic ring (R). The discrete geometries as pharmacophoric feature were developed and the generated pharmacophore model was used to derive a predictive atom-based 3D QSAR model for the studied data set. The obtained 3D QSAR model has an excellent correlation coefficient value (r(2)= 0.9995) along with good statistical significance which is indicated by high Fisher ratio (F= 8537.4). The model also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q(2) = 0.6919). The QSAR model suggests that hydrophobic character is crucial for the DPP-IV inhibitory activity exhibited by these compounds and inclusion of hydrophobic substituents will enhance the DPP-IV inhibition. In addition to the hydrophobic character, electron withdrawing groups positively contribute to the DPP-IV inhibition potency. The findings of the QSAR study provide a set of guidelines for designing compounds with better DPP-IV inhibitory potency.