The design and synthesis of αvβ6 antagonists and PI3K inhibitors as small molecule therapies for respiratory diseases

  • Christopher John Tame

Student thesis: Doctoral Thesis

Abstract

The respiratory system controls gas exchange in the process of respiration, a function essential for human life. Consequently, disorders in respiratory function significantly impact the quality of life and are often fatal. These disorders usually occur in the lungs, the major respiratory organ. Current treatments for respiratory diseases often possess undesired side-effects due to off-target biological activity, [1] whilst others are only suitable for specific patient populations. [2] Consequently, respiratory diseases are responsible for millions of hospitalisations and deaths every year. In the USA alone, the cost of asthma to the economy is estimated at {dollar}55 billion per year, and is increasing at a rate of over {dollar}3000 per person, per year. [3] Taken together with the substantial reduction in the quality of life associated with these disorders, it is clear that research towards improved treatments for respiratory diseases have the potential to significantly impact both patients and economies. This thesis presents scientific research towards the identification of small molecule therapies for two respiratory diseases, Idiopathic Pulmonary Fibrosis (IPF) and Asthma. Chapter 1 presents the design and synthesis of the first series of orally bioavailable αvβ6 selective antagonists for the treatment of IPF, whilst Chapter 2 concerns the design and synthesis of two orthogonal series of small molecule PI3K inhibitors for the treatment of asthma. The research aims were to identify safe and efficacious treatments that are also convenient for the patient to administer. Investigations have, therefore, focussed on selectively modulating a specific biological target and designing a suitable pharmacokinetic profile for oral delivery, where possible. The results presented in this document demonstrate significant advancements towards this goal, and offer encouragement that an improved standard of care for respiratory disorders is possible. The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents. [See thesis 'References' p. 402 for citations]
Date of Award1 Jan 2015
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde

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