P.433 Impact of sex in three paradigms evaluating the abuse and dependence potential of new chemical entities

Natural Products (NP), specifically from medicinal plants or herbs, have been extensively utilized to analyze the fundamental mechanisms of ultimate natural sciences as well as therapeutics. Isolation of secondary metabolites from these sources and their respective biological properties, along with their lower toxicities and cost-effectiveness, make them a significant research focus for drug discovery. In recent times, there has been a considerable focus on isolating new chemical entities from natural flora to meet the immense demand for kinase modulators, and also to overcome major unmet medical challenges in relation to signal transduction pathways. The signal transduction systems are amongst the foremost pathways involved in the maintenance of life and protein kinases play an imperative part in these signaling pathways. It is important to find a kinase inhibitor, as it can be used not only to study cell biology but can also be used as a drug candidate for cancer and metabolic disorders. A number of plant extracts and their isolated secondary metabolites such as flavonoids, phenolics, terpenoids, and alkaloids have exhibited activities against various kinases. In the current review, we have presented a brief overview of some important classes of plant secondary metabolites as kinase modulators. Moreover, a number of phytocompounds with kinase inhibition potential, isolated from different plant species, are also discussed.

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Synthesis of Indolyl Pyrazole Scaffolds as Potential Anti-cancer Agents and their Molecular Modelling Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180816666191024103534 ◽

2020 ◽

Vol 17 (7) ◽

pp. 828-839

Author(s):

Ganga Reddy Gaddam ◽

Pramod Kumar Dubey ◽

Venkata Ramana Reddy Chittireddy

Keyword(s):

Cell Lines ◽

Biological Activities ◽

Moderate Activity ◽

Lung Cancer Cell ◽

Anti Cancer ◽

A549 Lung Cancer Cell ◽

New Chemical Entities ◽

Molecular Modelling Studies ◽

Modelling Studies ◽

A549 Lung

Background:: Indole and pyrazoles are one of the prime structural units in the field of medicinal chemistry and have been reported to exhibit a variety of biological activities specifically anti-cancer. In view of their medicinal significance, we synthesized a conjugate of the two moieties to get access to newer and potential anti-cancer agents. Methods: Indolyl pyrazoles [3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(1-methyl-1H-indole-3-carbon yl)acrylonitriles] (4a-l) were synthesized by adopting simple and greener protocol and all the synthesized derivatives were docked against Bcl-2 protein and the selected chemical moieties were screened for their cytotoxicity by using the MTT assay. Results: : All the synthesized compounds were docked against BCL-2 protein in order to understand their binding pattern. Among the 12 compounds docked, 4d, 4f, 4h, 4j, and 4l compounds exhibited better protein binding interactions and the same were screened for their anti-cancer activity against A549 (lung) cancer cell lines at a concentration of 100 μM using Doxorubicin as standard. Substitutions such as N-benzyl, N-ethyl groups and halogen groups such as Br, Cl on indole ring showed moderate activity against A-549 cell lines. Conclusion:: Among the 5 indolyl pyrazole derivatives screened, compounds 4h and 4j showed significantly better activity with an IC50 of 33.12 and 34.24 μM, respectively. Further, structural tweaking of the synthesized new chemical entities may lead to potential hit/lead-like molecules.

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Self-microemulsion Technology for Water-insoluble Drug Delivery

Current Nanoscience ◽

10.2174/1573413715666190112122107 ◽

2019 ◽

Vol 15 (6) ◽

pp. 576-588 ◽

Cited By ~ 1

Author(s):

Beibei Yan ◽

Yu Gu ◽

Juan Zhao ◽

Yangyang Liu ◽

Lulu Wang ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Aqueous Solubility ◽

Delivery Systems ◽

Poorly Soluble Drugs ◽

New Chemical Entities ◽

Poorly Soluble ◽

Water Insoluble Drug ◽

Semi Solid ◽

Solidification Technology

: According to the drug discovery, approximately 40% of the new chemical entities show poor bioavailability due to their low aqueous solubility. In order to increase the solubility of the drugs, self-micro emulsifying drug delivery systems (SMEDDS) are considered as an ideal technology for enhancing the permeability of poorly soluble drugs in GI membranes. The SMEDDS are also generally used to enhance the oral bioavailability of the hydrophobic drugs. At present, most of the self-microemulsion drugs are liquid dosage forms, which could cause some disadvantages, such as the low bioavailability of the traditional liquid SMEDDS. Therefore, solid self-micro emulsifying drug delivery systems (S-SMEDDS) have emerged widely in recent years, which were prepared by solidifying a semi-solid or liquid self-emulsifying (SE) ingredient into a powder in order to improve stability, treatment and patient compliance. The article gives a comprehensive introduction of the study of SMEDDS which could effectively tackle the problem of the water-insoluble drug, especially the development of solidification technology of SMEDDS. Finally, the present challenges and the prospects in this field were also discussed.

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An overview of Osmotic Drug Delivery System: An update review

International Journal of Bioassays ◽

10.21746/ijbio.2017.07.001 ◽

2017 ◽

Vol 6 (7) ◽

pp. 5426 ◽

Cited By ~ 2

Author(s):

Hiren J. Patel ◽

Vaishnavi P. Parikh

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Life Cycle Management ◽

Delivery Systems ◽

Osmotic Pump ◽

Factors Affecting ◽

Advantages And Disadvantages ◽

New Chemical Entities ◽

History Of ◽

Novel Drug

The pharmaceutical industry has faced several marked challenges in order to bring new chemical entities (NCEs) into the market over the past few decades. Various novel drug delivery approaches have been used as a part of life cycle management from which Osmotic drug delivery systems look the most promising one. After discussing the history of osmotic pump development, this article looks at the principles, advantages and disadvantages of osmotic drug delivery systems. Then, the basic components of osmotic pump and factors affecting the design of oral osmotic drug delivery systems are discussed in detail. In the later part of the manuscript, various types of osmotic pumps available in the market and evaluation methods for osmotic drug delivery systems are discussed in detail.

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Oral tobacco: prevalence, health risks, dependence potential and public policy

Addiction ◽

10.1111/j.1360-0443.1990.tb03429.x ◽

1990 ◽

Vol 85 (9) ◽

pp. 1097-1098 ◽

Cited By ~ 7

Author(s):

ROBERT WEST ◽

KOFI KRAFONA

Keyword(s):

Public Policy ◽

Health Risks ◽

Dependence Potential

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Stereoselective Synthesis and Applications of Spirocyclic Oxindoles

Organic Chemistry Frontiers ◽

10.1039/d0qo01085e ◽

2021 ◽

Author(s):

Alexander Boddy ◽

James A Bull

Keyword(s):

Medicinal Chemistry ◽

Stereoselective Synthesis ◽

New Chemical Entities

The development of novel synthetic strategies to form new chemical entities in a stereoselective manner is an ongoing significant objective in organic and medicinal chemistry. This review analyses the development...

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The Role of Microscopy in Preclinical Safety Assessment

Microscopy and Microanalysis ◽

10.1017/s143192760003748x ◽

2000 ◽

Vol 6 (S2) ◽

pp. 998-999

Author(s):

Barbara J. Dovey-Hartman

Keyword(s):

Electron Microscopy ◽

Vital Role ◽

Pathology Report ◽

Clinical Phase ◽

Transmission Electron ◽

New Chemical Entities ◽

Regulatory Submissions ◽

Hematoxylin And Eosin ◽

Preclinical Safety

Microscopy plays a vital role in assessing the safety of New Chemical Entities (NCE) in the pre-clinical phase of drug development. Light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM) are used at the Schering-Plough Research Institute (SPRI) for evaluation of NCE. To support regulatory submissions, NCE are routinely tested in rodents in short-term studies such as one-month toxicity studies, and in longterm studies such as oncogenicity studies that may last 24 months. At the completion of a study, the animals are necropsied and the required tissues collected and stored in fixative. The tissues for LM are processed to slides and stained with Hematoxylin and Eosin (H&E). The information derived from the examination of these tissues by LM becomes an essential part of the pathology report. The LM examination of these tissues usually yields the information needed to either progress a NCE or otherwise deter or halt development.

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A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114552796 ◽

2014 ◽

Vol 20 (2) ◽

pp. 254-264 ◽

Cited By ~ 3

Author(s):

José Pérez ◽

Caridad Díaz ◽

Francisco Asensio ◽

Alexandra Palafox ◽

Olga Genilloud ◽

...

Keyword(s):

Drug Discovery ◽

Physicochemical Properties ◽

Safety Concern ◽

Aqueous Solubility ◽

Cyp3a4 Inhibition ◽

Use Of Resources ◽

Simultaneous Evaluation ◽

New Chemical Entities ◽

Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

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