Novel, Highly Potent Aldose Reductase Inhibitors:  (R)-(−)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 4-spiro-3‘-pyrrolidine-1,2‘,3,5‘-tetrone (AS-3201) and Its Congeners

Abstract

A series of novel tetrahydropyrrolo[1,2-a]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin-induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo[1, 2-a]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1, 2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10(-8) M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)-enantiomer 44 (SX-3202). From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single-crystal X-ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Then, the spirohydantoin-like spiroimide minalrestat was formed by the replacements of both the chroman and hydantoin with isoquinoline-1,3(2H,4H)-dione ring and succinimide ring, respectively, and the addition of benzyl side chain at the 2-position. Further replacement of the isoquinoline-1,3(2H,4H)-dione ring of minalrestat with pyrrolo[1,2-a]pyrazine-1,3(2H,4H)-dione led to ranirestat (AS-3201) [66]. Imirestat was withdrawn from clinical trials due to toxicity.…”

Development of Atom-Economical Catalytic Asymmetric Reactions under Proton Transfer Conditions: Construction of Tetrasubstituted Stereogenic Centers and Their Application to Therapeutics

“…[18][19][20][21][22][23] Our particular focus at the beginning of this project in 2006 was the establishment of a concise, practical, and enantioselective synthetic route to Ranirestat (AS-3201, 1), a highly potent aldose reductase inhibitor. [24][25][26] Whereas almost all the other candidate aldose reductase inhibitors were withdrawn during the course of clinical development, 1 was identified as a structurally novel aldose reductase inhibitor bearing a spirosuccinimide entity exhibiting remarkable efficacy and safety. 24) 1 is orally available and is under late-stage clinical trials in the U.S. and Canada for the treatment of diabetic neuropathy.…”

“…[24][25][26] Whereas almost all the other candidate aldose reductase inhibitors were withdrawn during the course of clinical development, 1 was identified as a structurally novel aldose reductase inhibitor bearing a spirosuccinimide entity exhibiting remarkable efficacy and safety. 24) 1 is orally available and is under late-stage clinical trials in the U.S. and Canada for the treatment of diabetic neuropathy. When we launched our study, the asymmetric synthesis of 1 relied on the optical resolution of racemic 2 through two cycles of recrystallization with cinchonidine, placing a severe limitation on the large-scale production of this highly potent therapeutic candidate (Chart 1a).…”

“…When we launched our study, the asymmetric synthesis of 1 relied on the optical resolution of racemic 2 through two cycles of recrystallization with cinchonidine, placing a severe limitation on the large-scale production of this highly potent therapeutic candidate (Chart 1a). 24) The structural feature of 1 is a stereogenic tetrasubstituted carbon bearing an amino functionality, and its catalytic asymmetric construction is the obvious key to the practical synthesis of 1. A retrosynthetic analysis of 1 indicated that the catalytic asymmetric amination of the succinimide derivative 3 was a viable approach to this end (Chart 1b).…”

Racemic Descriptors for Quantitative Structure Activity Relationship of Spirosuccinimide Type Aldose Reductase Inhibitors

“…5 Negoro et al synthesized tetrahydropyrrolo[1,2-a]pyrazine derivatives and performed the assay. 6 Although the spirosuccinimide cogeners contain the chiral center indicated by * in the figure of Table 1, the AR inhibition assay is performed with racemic mixtures.…”