Mayank Kumar Sharma

Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.

Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review.

Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimers disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.

Medicinal Chemistry Perspective of Fused Isoxazole Derivatives.

Nitrogen containing heterocyclic rings with an oxygen atom is considered as one of the best combination in medicinal chemistry due to their diversified biological activities. Isoxazole, a five membered heterocyclic azole ring is found in naturally occuring ibetonic acid along with some of the marketed drugs such as valdecoxib, flucloxacillin, cloxacillin, dicloxacillin, and danazol. It is also significant for showing antipsychotic activity in risperidone and anticonvulsant activity in zonisamide, the marketed drugs. This review article covers research articles reported till date covering biological activity along with SAR of fused isoxazole derivatives.

Virtual screening-based identification of lead molecules as selective TACE inhibitors

Some novel selective inhibitors of tumor necrosis factor-α converting enzyme (TACE) have been identified from virtual screening of Asinex database containing 2,06,759 compounds using HTS docking with TACE and MMPs and application of Lipinski’s rule of five. Docking studies were carried out for known inhibitors along with lead compounds. Pyrrolidine-based tartrate diamides were docked into the active site of TACE along with MMPs to get insight regarding the binding interactions of active and inactive TACE inhibitors. The 3D orientations of the obtained hits from virtual screening were found to match with that of known inhibitors supporting the binding of the hit molecules into the active site of TACE.

A comprehensive patents review on cannabinoid 1 receptor antagonists as antiobesity agents

Introduction: Obesity is a rapidly expanding worldwide health problem. Various targets are investigated presently for the treatment of obesity, but there remains an unmet need for an effective drug therapy with acceptable efficacy levels and reduced side effects. Targeting peripherally located cannabinoid 1 (CB1) receptors is an attractive strategy as these receptors play a vital role in energy homeostasis. Areas covered: CB1 receptor antagonists constitute one of the most important categories of compounds of interest for the control of obesity. In this review, the authors focus on recent advances (since 2007) in diverse chemical classes of patented compounds belonging to the category of CB1 receptor antagonists. Expert opinion: Safer CB1 receptor antagonists for the treatment of obesity can be discovered by developing such compounds that act peripherally. Increasing the polar service area, decreasing the lipophilicity and designing of neutral antagonists and allosteric inhibitors are some interesting strategies that could offer promising results.

Exploring structural requirements for peripherally acting 1,5-diaryl pyrazole-containing cannabinoid 1 receptor antagonists for the treatment of obesity

Peripherally acting cannabinoid 1 (CB1) receptor antagonists are considered as potential therapeutics for the treatment of obesity with desired efficacy and reduced central nervous system side effects. A dataset of 72 compounds containing the 1,5-diaryl pyrazole basic skeleton having peripheral CB1 receptor antagonistic activity was utilized for three-dimensional quantitative structure–activity relationship studies. Compounds of the series exhibited high variations in the biological activity and chemical structures. Different types of molecular alignments, such as atom-based, data-based, centroid-based and centroid/atom-based were utilized to develop the best CoMFA model. The best CoMFA model was obtained with a database alignment and the same alignment was further used for the development of a CoMSIA model. The best developed CoMFA model had

Structural requirements for imidazo[1,2-a]pyrazine derivatives as Aurora A kinase inhibitors and validation of the model

r^{2}_\mathrm{cv} = 0.552

New role of phenothiazine derivatives as peripherally acting CB1 receptor antagonizing anti-obesity agents

rcv2=0.552 with six components,