Anti-arthritic agents

ARRY-438162 is a recently disclosed potent and selective ATP non-competitive MEK1/2 inhibitor that is in Phase lb clinical trials as an anti-arthritic agent [24]. ARRY-438162 inhibited the MEK1/2 enzyme with an IC50 = 12 nM and pERK in cells with an IC50 = 11 nM. ATP non-competitive inhibition may be responsible for equipotent inhibition of MEK1/2 in vitro and pERK in cells. The compound was selective against a panel of 220 other kinases. 

Of interest here is that certain drugs and prodrugs that contain an isoxazole ring are metabolized to a cyano enol, e.g., leflunomide (11.122, R = CF3, R = H), a prodrug of the potential anti-arthritic agent 2-cyano-3-hydroxy-A-[4-(trifluoromethyl)phenyl]but-2-enamide (11.123). After oral administration of 50 mg/kg of 11.122 to rats, the plasma concentration of the prodrug peaked at 1 pg/ml and dropped rapidly, whereas the concentration of the active metabolite 11.123 was maintained at ca. 100 pg/ml for 24 h [147]. This... 

The potent anti-arthritic agent penicillamine (21) and the anti-nausea agent thalidomide (22) are drugs that have one stereogenic centre. For these compounds, one enantiomer [(S)-21 and (J )-22, respectively] is beneficial and the other is highly toxic (21) or induces severe pre-natal deformities (22). Draw stereo diagrams of (S)-21 and (/ )-22. 

Kaplan JM, Badger AM, Ruggieri EV, Swift BA, Bugelski PJ. Effects of SK E 105685, a novel anti-arthritic agent, on immune function in the dog. Int J Immnnopharmacol 1993 15 113-123. 

On the other hand, rat adjuvant-induced arthritis is a model of chronic inflammation frequently reported in screening for anti-arthritic agents. Adult rats are the animals of choice because the disease does not occur in hamsters, mice or guinea pigs. The clinical and pathological changes in adjuvant disease are comparable to those of rheumatic arthritis [56]. 

The patents by the same author disclose applications for previously reported Diels-Alder adducts obtained from the thioketen and cycloalkadienes, which are useful as anti-arthritic agents, and applications for azine- and carbodi-imide-thioketen adducts for imparting water repellancy to textiles. Further details of patented routes to the precursor from which the thioketen is synthesized (its dimer) have also appeared. ... 

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