Class of 2006 Abstract / Objectives: To investigate the types of information and resources either used or required for the management of products in the pipeline as perceived by decision-makers in the biotechnology and pharmaceutical (B&P) industries. More specifically, the objectives are to ascertain the strategic use of pharmacoeconomic (PE), financial, and decision- making tools and financing requirements amongst pipeline candidates. Methods: A study-specific survey instrument was used for the project. In detail, this survey is based upon the use of financial, PE, and decision-making tools for drug product development. Approximately 396 B&P firms were surveyed via postal mail, wherein the primary contact was the Chief Financial Officer (CFO). If the CFO was not listed on the firm’s website, the survey will be addressed to the Business and Development Officer (BDO) or Chief Executive Officer (CEO). The companies’ information will be identified by use of publicly-available databases. A modified form of a total survey design will be used for the postal mailings, including one initial mailing with a cover letter and survey, a follow-up reminder postcard, a second cover letter and survey for non-responders, and a final follow-up reminder postcard then after. Results: Survey instruments were completed by 20 firms, with 5 of them from public firms and 15 from the private sector. Capital and regulatory requirements and investor expectations are the most important factors considered during early and late phase clinical trials. Net present value (NPV) and internal rate of return (IRR) are the most commonly used financial analytic tools used for making research and development (R&D) decisions. PE are reported to be first used during all clinical phases prior to Food and Drug Administration (FDA) approval, and most drug candidates undergo formal PE evaluations. PE is also used in various areas of R&D and marketing components, such as licensing and go/no-go decisions. Capital/securities markets and venture capital (VC) are the primary sources of capital used in the development of a new drug. VC is important during all phases of R&D and numerous VC firms get involved. B&P firms disagree that VC companies should be involved with the managerial roles of the firm. Conclusions: It has been determined that the strategic use of PE, financial and decision-making tools, and capital requirements amongst pipeline candidates are important during all phases of R&D.

The high demand of novel peptide and peptidomimetics based on the amount of genomic and proteomic data need be matched by synthesis and screening. The design and synthesis of peptide and peptidomimetics are so important because the peptide and protein-protein interaction play a key role in molecule recognition and signaling. The modified peptides have better stability and pharmacokinetic properties which may be guided by rational design and molecular modeling. Now many organic and medicinal chemists have chosen peptide and peptidomimetics as potential drug candidates for many targets. In this dissertation, research efforts in design and synthesis of cyclic peptides with stabilized secondary structure have been investigated. Cyclization of linear peptides may restrict the number of available conformations which may improve the affinity attaching to the target. In this study, different beta turn linkers have been designed and synthesized to achieve more stable cyclic peptides with beta-sheet structures. Based on different beta turn linkers, analogs of cyclic peptides have been synthesized and screened. The structure activity relationships (SAR) of these cyclic peptide analogs have been studied. In chapter three, analogs of peptidomimetic inhibitors have been designed and synthesized. These peptide analogs are targetingHuman Rhinovirus (HRV) and Coronavirus (CoV) by inhibiting the cysteine protease. The docking and modeling studies have been shown. The structures of this kind of inhibitors include five fragments. The warhead provides the activity, which can covalently react with the thiol of cysteine protease and permanently eliminate its proteolytic activity. The warhead is linked to a peptide backbone including the other four parts that are designed to position the warhead where it can specially react with the critical thiol of the cysteine protease active site. The side chain of each amino acid has been optimized to achieve better solubility and permeability. We successfully synthesized some compounds with good potency.

Le profilage d’impuretés de candidats médicaments est une préoccupation majeure des industries pharmaceutiques. L’identification et la quantification des impuretés doivent être strictement contrôlées pour assurer l’efficacité et la toxicité limitée du principe actif. Il est donc nécessaire de disposer de méthodes analytiques performantes afin de s’assurer que l’ensemble des impuretés est identifié. L’HPLC phase inverse sur phase C18 reste aujourd’hui la méthode de choix pour cette tâche. Cependant, il arrive que cette méthode échoue, notamment lorsque le principe actif n’est pas suffisamment retenu sur la colonne ou que les impuretés ne sont pas parfaitement séparées du composé principal. Il est alors essentiel de pouvoir se tourner vers des méthodes analytiques alternatives et complémentaires.Ce travail de recherche traite du développement et de l’évaluation de méthodes analytiques alternatives à l’HPLC phase inverse sur phase C18 pour le profilage d’impuretés de principes actifs pharmaceutiques. L’HPLC phase inverse sur d’autres phases stationnaires, l’HPLC mixed-mode ainsi que la SFC ont été explorées et leurs performances chromatographiques comparées. La comparaison et l’étude des différentes méthodes ont permis de proposer une stratégie d’analyse du candidat médicament. / Impurity profiling of drug candidates is a significant concern of pharmaceutical industries. The identification and quantification of impurities must be strictly controlled to ensure the efficacy and limited toxicity of the active ingredient. It is therefore necessary to have efficient analytical methods to ensure that all impurities are identified. Today, reversed-phase HPLC with C18 column remains the method of choice for this task. However, this method sometimes fails, particularly when the active pharmaceutical ingredient is not sufficiently retained on the column or when the impurities are not resolved from the main compound. It is therefore essential to turn to alternative and complementary analytical methods.This work deals with the development and evaluation of alternative analytical methods to reversed-phase HPLC on C18 phase for impurity profiling of pharmaceuticals. Reversed-phase HPLC on other stationary phases, mixed-mode HPLC as well as SFC were explored and their chromatographic performances compared. The comparison and the study of the different methods allowed proposing a strategy of analysis of the drug candidate.

Autismspektrumtillstånd kännetecknas av kärnsymtomen stereotypa, repetitiva beteenden samt nedsatt förmåga att kunna hantera sociala relationer. Diagnostisering försvåras dock av att inga biomarkörer finns tillgängliga än. Forskning pågår för att få klarhet i patofysiologiska mekanismer, där funna defekta gener ger en bild av ökade svårigheter för nervcellen att reglera signaler efter behov. Behandling som riktar sig mot kärnsymtomen vid autismspektrumtillstånd finns ej, men forskning pågår för att hitta lämpliga läkemedel. Syftet med detta arbete var att sammanställa senaste forskningen inom detta område, via sökning efter dubbelblinda randomiserade kontrollerade studier, för att utvärdera om något läkemedel kommer finnas på marknaden inom en snar framtid. Studier med D-vitamin, bumetanid (diuretikum), suramin (antipurinergt), memantin ”extended release” (mot Alzheimers sjukdom), metylerad vitamin B12 och celecoxib (anti-inflammatoriskt) som adjuvans till risperidon (neuroleptikum) utvärderades för effekten på kärnsymtom vid autismspektrumtillstånd. Bumetanid, som är ett loop-diuretikum, var det läkemedel som kommit längre än övriga. Om även fas 3 ger positiva resultat så finns möjligheten att detta kan släppas på europeiska marknaden om några år för behandling av kärnsymtom vid autismspektrumtillstånd. Övriga substanser var i ett mycket tidigt utvecklingsstadium. / Autism spectrum disorder is characterised by the core symptoms stereotypic, repetitive behaviors and impaired ability to handle social relationships. Diagnostics, however, is complicated by the fact that no biomarkers are available yet, i.e. one cannot take a blood test to decide if the individual can be diagnosed with autism spectrum disorder. Research, however, is ongoing in this field hopefully also leading to markers that can be used when evaluating degree of severity during clinical research where potential pharmaceuticals are evaluated in humans. Research is ongoing to clarify pathophysiological mechanisms. Identified clusters of defective genes suggest increased difficulties of nerve cells to regulate signals as needed. For example, excitation or inhibition of nerve cells can be enhanced. Treatment aimed at the core symptoms of autism spectrum disorder is not available, but research is ongoing to find suitable drugs. The purpose of this work was to compile the latest research in this area through a search for doubleblinded randomized controlled studies to evaluate whether any drug will be available on the market in the near future. Studies with vitamin D, bumetanide (diuretic), suramin (antipurinergic), memantine “extended release” formulation (Alzheimer’s disease drug), methylated vitamin B12 and celecoxib (anti-inflammatory) as adjuvant to risperidone (neuroleptic) were evaluated for the effect on core symptoms in autism spectrum disorder. Bumetanide, which is a loop-diuretic, is the drug that has come further than the rest. If the continued development of this drug also gives positive results, there is the possibility that this drug can be released on the European market in a few years, for treatment of core symtoms. The other substances evaluated were at a very early stage of development. Some of these, however, can be of extra interest. For example D‑vitamin which can have some potential effect. Also it gives minimal side effects.