Current patent literature

Recent patent disclosures detail extensive efforts directed toward surrogates (63-68) for the phenylacetic acid moiety of GW3965, as exemplified by indole 63 [154], isoxazole 64 and pyrazole 65 [155], and encompasses quinolines or tetra-hydroquinolines (i.e. 67) [156] as the most preferred analogs. Interestingly, the carboxylic acid of GW3965 was also removed or converted into amines and amides. Significantly, the patent covering indoles such as 63 discloses new modifications for the amino terminus, arene substituent optimization, the replacement of the ben-zhydryl moiety with an a-phenethyl group, and exploration of specific methyl substitution (e.g. R1, R2 and R3) throughout aliphatic linker region of 63 [154]. Interestingly, a recent patent application disclosed that GW3965 suppresses IL-13 overproduction and decreases IL-13 concentrations in bronchoalveolar lavage fluid, supporting a claim for the treatment of eosinophilia [157].

In extensions of the T-1317 aniline SAR, the sulfonamide was replaced with an aryl-substituted tertiary amine 69 [158]. A second patent further expands the scope where the most preferred analogs incorporate the aniline nitrogen into an indole ring (i.e. 70) [159]. Separately, the nitrogen was also incorporated into an quinazoli-none (71) [160]. In addition to these early structural templates, a host of new agonist classes with heteroaryl cores have been claimed (as exemplified by indazole 72 [161], quinoline 73 [162], pyrazole 74 [163] and thiadiazole 75 [164]. Substantial numbers of related analogs of 73 and 75 were synthesized, but the specific claims did not narrow the patent's scope. Amide agonists were reported with specific reference to their LXRß activity as exemplified by 76 [165]. Separately, a set of adamantine amides were disclosed, as illustrated by 77, with varied regioisomers of the furyl and pyridinyl rings claimed [166].




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