Prodrugs Design | Chapter 11 | Modern Advances in Pharmaceutical Research Vol. 2

Prodrug design can be used in the following cases: improving active drug solubility and consequently bioavailability, increasing permeability and absorption and modifying the drug’s distribution profile. In the prodrug design, a computational approach consisting of calculations using Molecular Orbital (MO) and Molecular Mechanics (MM) methods and correlations between experimental and calculated values can be utilized.

Author(s) Details

Professor Rafik Karaman
Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine and Department of Sciences, University of Basilicata, Viadell’Ateneo Lucano 10, 85100, Potenza, Italy.

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The Question of Prodrug Naming | Chapter 07 | Modern Advances in Pharmaceutical Research Vol. 2

Prodrug is a term used to define a pharmacologically inactive chemical entity that can be used to temporarily alter the physicochemical properties of a drug to increase its usefulness and decrease its associated toxicity. According to the definition, the inactive prodrug converts to its active parent drug and a non-toxic linker upon exposure to a physiological environment. Albert stated in his Selective Toxicity book, that the term prodrug is incorrect and should be replaced with the term predug. He apologized for having invented the term, however, now it is too widely used to alter.

Author(s) Details

Professor Rafik Karaman
Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine and Department of Sciences, University of Basilicata, Viadell’Ateneo Lucano 10, 85100, Potenza, Italy.

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Prodrugs Designed by DFT and Molecular Mechanics Methods | Chapter 05 | Modern Advances in Pharmaceutical Research Vol. 2

The accumulation of knowledge on intramolecular processes, enzymes and transporters along with the vast progress in molecular revolution have accelerated the search for prodrugs having the capability to replace their corresponding current marketed drugs and to provide therapeutics with better pharmacological profiles. Utilizing the different available computational methods has led to the design and synthesis of a variety of prodrugs to replace their corresponding parent drugs.

It has been proven that prodrugs can significantly improve the life quality of patients.

The directed enzyme prodrug therapy (DEPT) approach to employ the design of artificial enzymes to activate prodrugs at specific sites along with use of intramolecular processes to design prodrugs are the most attractive strategies to obtain more efficient therapeutics.

Author(s) Details

Professor Rafik Karaman
Department  of  Bioorganic  Chemistry,  Faculty  of  Pharmacy,  Al-Quds  University,  P.O.Box  20002,  Jerusalem,  Palestine and Department of Sciences, University of Basilicata, Via dell’ateneo Lucano 10, 85100, Potenza, Italy.

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The Future of Prodrugs Design | Chapter 03 | Modern Advances in Pharmaceutical Research Vol. 2

When knowledge fails to provide answers to important questions such as how to improve the bioavailability of vital medications, “Imagination is more important than knowledge,” as Albert Einstein once said. Ingenuity in the design of effective prodrugs has been lacking in quantity and quality. The reasons behind the low quality of ingenuity could be related to the fact that medicinal chemists have expertise in organic and organometalic chemistry not in biochemistry and biology. On the other hand, pharmaceutical chemists, biologists and biochemists do not have the expertise to make sophisticated chemical devices. Therefore, in order for a prodrug strategy to work, a team consisting of all this expertise is necessary.

Author(s) Details

Professor Rafik Karaman
Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine and
Department of Sciences, University of Basilicata, Viadell’Ateneo Lucano 10, 85100, Potenza, Italy.

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Drug Delivery Approaches | Chapter 01 | Modern Advances in Pharmaceutical Research Vol. 2

This review discusses the different biological barriers that affect the delivery of therapeutic agents through membranes, such as intestinal mucosa, Brain Blood Barrier (BBB), and mediators of transport such as efflux transporters and the approaches for overcoming such barriers. The approaches illustrated in this review include: utilizing natural occurring transporters to deliver drugs specifically to their targets, nucleoside analogues delivery, CYP-activated prodrugs that target drugs to the liver, modification of passive diffusion by efflux pumps, intestinal transporters such as PEPT1 and GLUT1, Carrier Mediated Transport (CMT) systems for transporting nutrients, vitamins or hormones into the central nervous system, tissue selective drug delivery, administration of an exogenous enzyme to reach the tumor site which is followed by systemic administration of non-toxic prodrugs (ADEPT, GDEPT and VDEPT), enzymes involve in the bioconversion of ester-based prodrugs for activation (hydrolysis) of prodrugs to their active forms, brain targeted Chemical Delivery Systems (CDS), amino acid prodrugs to improve oral bioavailability, sustained drug delivery and intravenous drug delivery. Furthermore, Receptor-Mediated Transcytosis (RMT) for efficacious delivery of Nano particles via the intestinal mucosa and BBB, and the prodrug chemical approach based on intra molecularity to deliver anti-cancer drugs is discussed.

Author(s) Details

Professor Rafik Karaman
Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine and Department of Sciences, University of Basilicata, Viadell’Ateneo Lucano 10, 85100, Potenza, Italy.

Wajd Amly
Department of Bioorganic Chemistry, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine.

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Prodrugs-Current and Future Drug Development Strategy | Chapter 7 | Modern Advances in Pharmaceutical Research Vol. 1

The  focus  of  traditional  prodrug  approach  was  on  altering  various  physiochemical  parameters, whereas the current modern computational approach considers designing prodrugs through attaching appropriate  linkers  with  drugs  having  poor  bioavailability  which  upon  exposure  to  physiological environments release the parent active drugs in a programmable (controlled) manner resulting in an improvement of their bioavailability. With the possibility of designing prodrugs with different linkers, the release rate of the parent active drugs can be controlled. The future of  prodrug  technology  is  exciting  and  yet  challenging. Advances must be made in understanding the chemistry of many organic reactions that can be effectively utilized to enable the development of more types of prodrugs. The understanding of organic reaction mechanisms of certain processes, particularly intramolecular reactions, will be the next major milestone in this field. It is envisioned that the future of prodrug technology holds the  ability  to  create  safe and  efficacious delivery of a wide range of active small molecules and biotherapeutics. This goal can be achieved using computational chemistry methods such as ab initio, semi-empirical and density functional theory (DFT), and molecular mechanics (MM) to calculate physicochemical and molecular  properties of current marketed drugs suffer low bioavailability or/and unpleasant taste or odor.

Author(s) Details

Professor Rafik Karaman
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Palestine and Department of Science, University of Basilicata, Potenza, Italy.

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