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H. Jin, P. F. Kador, M. Wyman, K. Blessing; Optimized Synthesis of Topical Aldose Reductase Inhibitor KINOSTAT ® and Its Preliminary Clinical Evaluation in Diabetic Dogs. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1468.
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Diabetic dogs rapidly form bilateral sugar cataracts within one year of diagnosis. Similar cataracts rapidly form in galactosemic dogs where they can be reduced in a dose-dependent manner with the aldose reductase inhibitor (ARI) 6-fluoro-2,3-dihydro-2-methyl-(2R,4S)-spiro[4H-1-benzo-pyran-4,4'-imidazolidine]-2',5'-dione (2MS). Since this compound is not commercially available, the compound is obtained in 3% overall yield through an established 11 step synthesis. The purpose of this study was to develop a more rapid synthesis of this compound and evaluate the ability of this compound to reduce sugar cataract when topically applied to diabetic dogs.
Starting with the synthetic procedures as outlined by Ueda et al (Fr. Demande, 1982), and Dirlam et al. (J.Org. Chem., 1987) synthetic modifications were conducted by replacing chymotrypsin resolution with a selective crystallization. A new stereochemical synthesis was subsequently developed which utilized a catalytic enantioselective Strecher reaction reported by Kato et al (Tetra. Let., 2004). The final product was prepared as a topical formulation (Kinostat ®) and is currently being clinically administered in a masked fashion to 20 recently diagnosed diabetic dogs. An additional 10 diabetic dogs are similarly being administered only topical vehicle in masked fashion. The protocol calls for the treatment of each dog to be unmasked after that dog develops cataracts.
2-MS contains two chiral centers at the 2 and 4 position. While the 2-chiral center is stereoselectively introduced at the first step of the synthesis, the center at the 4-position is resolved at the ninth step of the synthesis. Utilizing a selective crystallization step to replace the resolution step with chymotrypsin reduced the overall synthesis from 11 to 8 steps and increased the overall yield from 3% to 5.6%. Alternatively, the 4-chiral center was stereoselectively introduced by reaction of (R) 6-fluoro-2, 3-dihydro-2-methylchromen-4-one through an enantioselective Strecker synthesis. This resulted in an alternate 8-step synthesis with even greater yield. The 2-MS obtained by both modifications were identical to that obtained through the original procedures
A more rapid a cost effective synthesis of 2-MS has been developed. Preliminary results from the ongoing clinical evaluation of the topical administration of Kinostat ® suggest that this compound reduces the progression of cataracts in diabetic dogs since all dogs unmasked to date have been on placebo.
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