Kishore V. L. Parsa

Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of Type 2 Diabetes.

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic beta-cells and subsequent lowering of blood glucose levels, HbA[1(c)], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.

Francisella tularensis Induces IL-23 Production in Human Monocytes

Francisella tularensis, the causative agent of tularemia, is phagocytosed by immune cells such as monocytes and macrophages. Instead of being destroyed in the phagolysosome, the bacterium escapes the phagosome and replicates within the host cytosol. Recent studies indicate that phagosomal escape may have a major impact on the nature of the inflammatory cytokine response to infection. To better understand the host cell response to Francisella infection, we exposed human peripheral blood monocytes to Francisella novicida and analyzed transcriptional changes using high-density oligonucleotide microarrays. Results showed a nearly 300-fold up-regulation of transcripts for the p19 subunit of IL-23, and a nearly 18-fold up-regulation for the p40 subunit of IL-12. IL-23 is formed by the heterodimerization of p19 and p40, and is an important cytokine of the innate immune response. Up-regulation of p19 and p40 was confirmed at the protein level by Western blotting and ELISA analyses, and was found to be largely dependent on PI3K and NF-κB activity. Studies using medium from infected monocytes with or without a p19 blocking Ab showed that the secreted IL-23 induced IFN-γ production from NK cells, suggesting a potential biologically important role for IL-23 in host defense. Finally, infection of human monocytes by the highly virulent Francisella SCHU S4 strain likewise led to IL-23 production, suggesting that the IL-23 response may be relevant during tularemia.

Pd-mediated new synthesis of pyrroles: their evaluation as potential inhibitors of phosphodiesterase 4

A sequential Pd-mediated multi-component reaction followed by Suzuki or Heck or Sonogashira coupling in a single pot has been developed for the synthesis of functionalized pyrroles as potential inhibitors of PDE4.

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.

Negative regulators of toll-like receptor 4-mediated macrophage inflammatory response

Activation of macrophages through TLR4, the receptor for the bacterial endotoxin LPS, results in a potent inflammatory response aimed at eliminating the invading pathogen. Excessive production of inflammatory mediators is harmful to host tissue and in extreme cases can result in fatal outcomes. This inflammatory response is, therefore, tightly regulated by negative regulatory mechanisms that act to maintain homeostasis. This review will summarize recent advances in our current understanding of molecular mechanisms that regulate macrophage TLR4 signaling.

Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives from nimesulide (and their 2-oxo analogues): A new strategy to identify inhibitors of PDE4B

A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.

Pyrrolo[2,3-b]quinoxalines as inhibitors of firefly luciferase: Their Cu-mediated synthesis and evaluation as false positives in a reporter gene assay

2-Substituted pyrrolo[2,3-b]quinoxalines having free NH were prepared directly from 3-alkynyl-2-chloroquinoxalines in a single pot by using readily available and inexpensive methane sulfonamide (or p-toluene sulfonamide) as an ammonia surrogate. The reaction proceeded in the presence of Cu(OAc)(2) affording the desired product in moderate yield. The crystal structure analysis of a representative compound and its supramolecular interactions are presented. Some of the compounds synthesized exhibited inhibitory activities against luciferase that was supported by the predictive binding mode of these compounds with luciferase enzyme through molecular docking studies. The key observations disclosed here can alert users of luciferase reporter gene assays for possible false positive results due to the direct inhibition of luciferase.

Ligand/PTC-free intramolecular Heck reaction: synthesis of pyrroloquinoxalines and their evaluation against PDE4/luciferase/oral cancer cell growth in vitro and zebrafish in vivo

A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecular Heck cyclization strategy was used to prepare these compounds, some of which showed significant inhibition of PDE4B (IC50≈ 5-14 μM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos.

Yb(OTf)3 mediated MCR: a new and regioselective approach towards polysubstituted pyrroles of pharmacological interest

A regioselective synthesis of 1,2,3,4-tetrasubstituted pyrroles has been achieved via Yb(OTf)3-mediated 3-component reaction of amines, a 1,3-diketone and phenacyl bromide in a single pot. Yb(OTf)3 was identified as a reusable catalyst and a number of pyrrole derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound confirmed the substitution pattern on the central pyrrole ring. The crystal structure analysis of the same compound indicated the presence of a sheet-like molecular arrangement along the bc-plane present in the molecule. A possible mechanism for the regioselective formation of 1,2,3,4-tetrasubstituted pyrrole rings is discussed. A number of compounds synthesized showed PDE4 inhibitory properties when tested in vitro and two of them were identified as inhibitors of further interest.

Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation.

Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.