Haydn W. R. Williams

Conformational Analysis of Leukotrienes and Related Compounds for Mapping the Leukotriene D4 Receptor: Application to the Design of Novel Anti-Asthma Drugs

Leukotrienes D4 (1a) and E4 (1b) are potent contractile substances which have been implicated in the ethiology of human asthma. These leukotrienes exert their effects through interaction with specific receptors on pulmonary smooth muscle and other tissues and thus the design of specific antagonists of these receptors offers the potential for the discovery of novel anti-asthma drugs. We have undertaken to characterize and map the LTD4 receptor via a variety of means. These include (a) analysis of structure-activity of the leukotrienes and of known LTD4 antagonists; (b) physical characterization of the receptor using radioactive labelled agonists and antagonists and (c) NMR and molecular modelling conformational analysis studies on leukotriene agonists and antagonists. The initial studies allowed us to propose a hypothetical model of the LTD4 receptor which was instrumental in the design of MK-571 (2), a LTD4 receptor antagonist which has undergone clinical testing. We have subsequently attempted to further refine this model using MK-571 and novel synthetic agonists at the LTD4 receptor as tools for such studies.

Synthesis of 2,3,4,4a,9,9a-hexahydro-3,9-methano-1H-indeno[2,1-c]pyridine and some N-substituted derivatives

The construction of the very rigid 2,3,4,4a,9,9a-hexahydro-3,9-methano-1H-indeno[2,1-c]pyridine system by three different routes is presented. One of the routes led also to another novel azabenzotricyclodecane system, viz. to the compound 2-(p-tolylsulphonyl)-1,2,3,3a,8,8a-hexahydro-3,8-ethanoindeno[1,2-c]pyrrole, which was the result of a skeletal rearrangement. The last of the routes gives easy access to the title compound and its derivatives.