Said, Najeeb Barrah; (1997) The design and synthesis of non-peptide bradykinin B2 receptor antagonists. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is a nonapeptide with a number of important biological actions. BK has been shown to act as a pathological mediator of pain and inflammation and thus drugs which can block this action of BK have a potential role as novel analgesics. HOE140 (Icatibant; D-Arg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-D-Tic7-Oic8-Arg9) is one of the most potent BK B2 receptor antagonists to have been synthesised. The unnatural amino acids at positions 7 and 8, D-Tic and Oic, are believed to induce a C-terminal β-turn which is thought to be responsible for its high binding affinity. A non-peptide antagonist of BK would offer a number of advantages over HOE140, including better oral bioavailability and increased metabolic stability. Our attempts at synthesising a non-peptide BK antagonist modelled on the C-terminal β-turn present in HOE140 are described. Two recent literature reports on the use of the 1, 4-benzodiazepin-2-one (BZD) scaffold to mimic a peptide reverse turn are outlined. These reports have been used to formulate a hypothesis that the C-terminal β-turn in HOE140 can be replaced by the BZD scaffold to form a non-peptide antagonist of BK. Two overlay models of the BZD scaffold on the C-terminal β-turn in HOE140 are provided and the synthesis and biological evaluation of over forty BZD ligands based on these models are described. Moderate biological activity was achieved with only the third compound tested, with Compound 61 exhibiting a Ki of 9.2 μM at the human BK B2 receptor. Analogues of this compound with a variety of C3 and N1 side chains on the BZD system are reported, as are compounds varying at the C5 position. These analogues were synthesised by changing either the amino acid or 2-aminobenzophenone portion of the BZD or by alkylating the BZD with a different electrophile. These studies have resulted in the synthesis of a more potent analogue, 121, with a sub-micromolar binding affinity: compound 121 has a Ki of 0.95 μM at the human BK B2 receptor. The structure activity relationships of the compounds tested are discussed and the attempts to optimise the biological activity are summarised. Preliminary studies on the alkylation of the C3 position are also documented. In describing the direct conversion of a second generation peptide antagonist into a non-peptide lead, this work has provided another example of a "privileged structure" furnishing useful leads in the search for new receptor-binding ligands.

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