The rational approach to the design and synthesis of NK-1 receptor antagonists and HIV-1 protease inhibitors / Wenqing Yao.

Yao, Wenqing.
2 v. (xxv, 490 p.) : ill. ; 29 cm.
Local subjects:
Penn dissertations -- Chemistry.
Chemistry -- Penn dissertations.
Chapter one focuses on the transformation of a selective peptidal somatostatin (SRIF) receptor ligand 4 into a potent and selective NK-1 receptor antagonist 5 via polyvalent nonpeptidomimetics 1 and 2. Our studies and the study of others support the hypothesis that the somatostatin receptor (SSTRs) and the substance P receptor (NK-1) share a topologically similar binding site for small ligands not revealed by their endogenous ligands. This suggests that a common binding site within the transmembrane domain of G protein-coupled receptors can be utilized to fashion potent agonists and antagonists, respectively. In addition, our results also demonstrate the power of the library method, even on a mini scale, not only to discover leads, but also to optimize structure activity relationships of the leads.*
Chapter 2 presents the design and synthesis of the first tricyclic peptide 24 as a potential SRIF antagonist by incorporating a significant conformational distortion in SRIF. The highlight of the synthetic strategy involved the five dimensional orthogonal amino protection and three carboxyl protecting groups to allow the selective closure of the three rings and differentiation of the two lysine side chains. t-Boc/t-Butyl, Alloc/Allyl, and finally trityl/2-chlorotrityl solid support as amine and carboxyl protecting group pairs were employed towards the synthesis of tricyclic peptide 24.*
Chapter 3 describes a novel approach toward the rational design and synthesis of active site directed HIV-1 protease inhibitors 58 and 82 via incorporation of an $\alpha$-diketone moiety at the p3$\sp\prime$ position of the reversible HIV-1 protease inhibitor 54. Compound 58 was found to be one of the most potent HIV-1 protease inhibitors described to date with IC$\sb{50}$ and CIC$\sb{95}$ of 75 pM and $<$6nM respectively. However, whether or not covalent bonds are indeed formed between the $\alpha$-diketone inhibitor 58 or 82 and the guanidine group of the Arg$\sp8$ or Arg$\sp{108}$ of HIV-1 protease remains to be verified.*
The central focus of Chapter 4 is to employ rational design and syntheses of peptidomimetics such as 110-111 as a tool to determine the influence of the secondary amide bond of the peptide on cell membrane transport. Our study supported an earlier hypothesis proposed by Stein and others that the higher desolvation energy, due to the formation of potential hydrogen bonding with water, is one of the main causes of poor absorption of the peptide from aqueous medium to the lipid phase of cell membrane. It was also suggested that this passive transport could be enhanced by reducing the hydrogen-bonding potential of the drug through the amide bond mimetic approach.* ftn*Please refer to the dissertation for diagrams.
Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 1996.
Includes bibliographical references and index.
Local notes:
University Microfilms order no.: 97-13029.
University of Pennsylvania.
Location Notes Your Loan Policy
Description Status Barcode Your Loan Policy