Saligenins

The saligenin head group has been used with success to prepare long acting |b2-adrenoceptor agonists with salmeterol playing a prominent role as a benchmark compound. In this connection, the combination agent AdvairTM (salmeterol and fluticasone) is currently in third place globally in terms of sales, demonstrating the success of this approach.

A common tactic employed to initiate research in this area has been to emulate salmeterol and modify its scaffold to improve the duration of action of the corresponding derivatives. A number of patent applications have issued which claim compounds with enhanced duration of action. The design principles which were used to derive these new analogues build on the observations that increased lip-ophilicity leads to extended the duration of action. Since little supporting biological data are provided in these applications, it is difficult to assess any improvements relative to salmeterol or formoterol. The disclosure which describes compound 13 also claims specific salts with supporting physical data, suggesting a higher level of interest in this analogue [28]. Further evidence for interest in this dichloro expression is a second filing where alternative head groups to the saligenin are exemplified, in particular the formamide head group that appears in formoterol [29]. Another transformation that has been pursued to increase the lipophilicity of salmeterol is to add additional alkyl substituents to the ether linkage as exemplified in 14 [30].

Researchers have been creatively replacing the alkyloxyalkyl linker of salmeterol with alternative expressions such as the phenethyl moiety in compound 15 and the conformationally constrained benzodioxane ring in analogue 16 [31,32].

If compound 15 has a similar binding mode to that of 1 and 13, it would suggest that the ^-adrenoceptor is tolerant of different substituents of the boxed phenyl ring. There are a number of patent filings which claim a wide variety of heterocycles and polar substituents appended to this phenyl ring, such as compound 17 [33]. The application containing cyclopentylsulfone analogue 18 claims the preparation of seven different salts, suggesting a high level of interest in this particular compound [34].

Diphenylanilines, exemplified by 7 have been the subject of follow-up studies. In particular, alternative substitution patterns around the diphenylaniline moiety have been discovered and these new findings have been extrapolated to other head groups. More complex substituents have also been appended, as in 19; it also appears that these diphenylaniline expressions can be successfully combined with the saligenin head group [35].

Recently published patent applications demonstrate the continuing interest in the saligenin expression, exemplified in 20, a potent ^-adrenoceptor agonist (EC50 = 0.058 vs. 0.100 nM for 20 and 1, respectively, in CHO cells recombinantly expressing the human ^-adrenoceptor) that incorporates the saligenin head group and a novel indole linking group to a dimethoxy-substituted benzylamide [36,37]. A recent poster publication disclosed additional in vitro EFS guinea-pig trachea data for 20, including potency relative to isoprenaline (RP = 0.021) and salmeterol-like duration of action [38]. The poster publication also speculated on the origins of the observed in vitro duration of action and concluded that exo-site binding and/or lipophilicity-driven tissue deposition may contribute toward the potential for long duration of action in humans [21].

Compounds including 21 (EC50 = 0.017 nM) have been identified that retain the saligenin head group, but replace the indole linker with a phenethylamine moiety that is substituted with a variety of aromatic and aliphatic amide tail groups [39-41].

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