In this paper, we provide an overview of the DMPK lead optimization process that is used to support drug discovery projects at Schering-Plough. Continuation of SAR and SPR studies identified additional 4 1H -quinolones suggesting that the microsomal stability of the compounds is as important for in vivo efficacy as the aqueous solubility.
In this review, we present a general screening paradigm that is currently being used as part of drug discovery at Schering-Plough and we describe a case study using the Hepatitis C Virus HCV protease inhibitor program as an example.
Introduction Lead optimization in a drug metabolism environment is a multifaceted operation. George Njoroge Find articles by Write an account of lead discovery and optimization techniques.
The staggering mortality rates combined with the global emergence of chemical resistance that the parasite Plasmodium falciparum has developed towards many of the common antimalarials compelled us to extend our research efforts to this growing problem.
Along with the advancement of chemistry and biology, new automated in vitro activity screening tools have become commercially available which can carry out complex, programmable and adaptable robotic operations to test hundred of thousands of compounds in a speedy and precise manner.
These studies have opened the doors to several possibilities regarding the 4 1H -quinolone scaffold optimization for future antimalarial development. Theses studies not only highlight the effectiveness of detailed SAR and SPR strategies used in drug discovery programs, but they also showcase the importance of re-evaluating historic antimalarials and exploiting their shortcomings.
Lead Generation as a Part of New Drug Discovery Contemporary parallel and combinatorial chemical synthesis produces large arrays of compounds that are available for evaluation in new drug discovery.
This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http: Find articles by K. Multiple synthetic routes were devised and implemented which enabled the rapid preparation and isolation of over structurally diverse 4 1H -quinolones and 1,2,3,4-tetrahydroacridones.
Through these optimization efforts using both SAR and structure-property relationship SPR studies, a more suitable candidate was developed that had superior physicochemical properties. Our drug design approach included not only the identification of liabilities of historic compounds but also the synthesis and optimization of numerous analogs guided by SAR.
Abstract Lead optimization using drug metabolism and pharmacokinetics DMPK parameters has become one of the primary focuses of research organizations involved in drug discovery in the last decade. It typically involves the use of various in vitro and in vivo screens to assess the drug metabolism and pharmacokinetic DMPK properties of multiple compounds, as well as to provide an early check on the safety issues that can be assessed in a higher throughput manner [ 1 — 4 ].
There are over million cases annually and over one million deaths. However, our approach focuses on the optimization of historic antimalarials such as endochin, floxacrine, or ICI 56, which possess liabilities such as lack of poor solubility, poor in vivo activity or lingering toxicity issues.
The need for identifying and developing new antimalarial drugs is very important. White Find articles by Ronald E.
Insights from both the antimalarial activity as well as the physicochemical properties determined which analogs would be advanced in the design process. As a result, these new forces have worked together to increase our ability to create new chemical entities NCEs that exhibit the targeted pharmacological activity.
Preliminary data from in vitro screening at the Walter Reed Army Institute of Research identified several chemotypes including 4 1H -quinolones and 1,2,3,4-tetrahydroacridones to have potent antimalarial activities.
Several of the compounds described in this work are currently being subjected to stringent head-to-head comparative studies to determine the analog best suited for pre-clinical trials.
The goal of these efforts is to find a compound that is suitable for development. Drug Metabolism as a Part of New Drug Discovery Several review articles in recent years have described the role that a drug metabolism and pharmacokinetics DMPK department can play in the process of new drug discovery [ 124 — 11 ].
The goal of the interaction is to find a molecule that has the desired biological activity as well as DMPK properties and a safety profile appropriate for the targeted therapeutic indication.
Graduate Theses and Dissertations. Korfmacher Find articles by Walter A. In addition, DMPK scientists may also use various screens to understand the potential of NCEs for preclinical or clinical toxicity [ 12 ].
Unfortunately, this compound failed to reduce parasitemia levels in P. Compared to endochin, which possesses EC50s of 8. Our research towards discovering and optimizing antimalarials was inspired from the severe impact malaria has had on our planet especially on impoverished countries.
All compounds were tested in vitro for antimalarial activity and characterized in parallel for physicochemical properties such as solubility, permeability, and logD7.
Based on our early investigations, 6-chloromethoxyphenyl-4 1H -quinolone emerged as a promising hit.Ashutosh Kumar Patidar et al.: Lead Discovery and Lead Optimization: A Useful Strategy in Molecular Modification of Nonrandom screening It is a modified form of random screening which was developed because of budgetary and manpower.
What is the latest in lead-finding technologies? How well do they work vs.
classical medicinal chemistry techniques? Where do you use techniques such as fragment-based lead discovery, DNA-encoded libraries, covalent binders, in silico screening, and artificial intelligence (AI)?
Lead discovery and optimization strategies for peptide macrocycles Peptide macrocycles offer some key advantages in both lead discovery and lead optimization phases of drug discovery when compared to natural product and synthetic macrocycles.
that ensures going after targets that capitalize on the unique properties of peptides coupled. This chapter describes techniques of discovering active com-pounds through screening and selecting the most promising compounds as leads.
The overall process is collectively known as lead discovery. promising hits for the lead optimization stage. In-house Libraries. The goal of our research endeavor was to successfully employ modern lead discovery and optimization strategies towards the development and identification of compounds possessing antimalarial activity.
Preliminary data from in vitro screening at the Walter Reed Army Institute of Research identified several chemotypes including 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones. Overall Drug Discovery and Development Process Candidate Development Commercialization III Submit Global Launch Global Optimization Lead Optimization First Human Dose Phase IA Phase IB/II.
Areas of Collaboration In Drug Development Pre-Clinical Development Phase 1 Phase 2 Phase 3 FHD FED Launch nd ng tion d Biology of Disease.Download