Sorbitol Dehydrogenase Inhibitors (SDIs):  A New Potent, Enantiomeric SDI, 4-[2-1R-Hydroxy-ethyl)-pyrimidin-4-yl]-piperazine-1-sulfonic Acid Dimethylamide

Abstract

We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure-activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10x more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.

A Sorbitol Dehydrogenase Inhibitor of Exceptional in Vivo Potency with a Long Duration of Action: 1-(R)-{4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl}ethanol

“…At 0.1 mpk, 16 and 16a gave 96% and 56% fructose inhibition, respectively. These results, taken together with the observed lack of turnover of 16 by rat microsomes in vitro 17 to generate 16a, are consistent with previous experience with 1c 5 as well as with 11a, regarding oxidoreduction of the monochiral hydroxyethyl. The aggregate contribution of favorable factors toward the striking in vivo potency enhancement of 16 over 2a, underpinning our design rationale, includes enhanced in vitro potency of SDH inhibition, reduced in vivo generation of less potent diastereomer metabolites, optimally increased log P to enhance nerve tissue penetration, and sufficiently lowered pK a to curtail extent of charged species at physiological pH.…”

“…5 Because both SDIs 1a and 1c feature a metabolically labile N,N-dimethylsulfamoyl group, 10 a metabolically stable replacement for the N,N-dimethylsulfamoyl group became a focal point for discovery of highly potent inhibitors with longer serum half-lives. Other factors that govern oral in vivo potency in target tissues, e.g., peripheral nerve, include the inhibitor's extent of absorption into systemic circulation, protein binding, pK a , and sufficient lipophilicity to efficiently partition from blood to tissues.…”

Anticataract Activity of Analogs of a Sorbitol Dehydrogenase Inhibitor

“…S-880773 (SDI-1) and CP-166,572 (SDI-2) were gifts from Hoechst A.G. (Frankfurt am Main, Germany) and Pfizer Cen- tral Research (Groton, CT), respectively. Additional amounts of SDI-1 and SDI-2 were synthesized according to outlined procedures (9,10), and were identical to S-88-0773 and CP-166,572 received. N,N,-dimethylsulfamoyl chloride, 1-N,N-dimethylsulfamoylpiperazine, 4-chloro-2,6-dimethoxypyrimidine, and 1-(2-pyrimidyl)-piperazine were purchased from Sigma-Aldrich (St. Louis, MO).…”

“…1). Our rationale was based on studies which suggest that the 2-hydroxymethyl group connected to the pyrimidine ring and the 1-position nitrogen of the pyrimidine ring are required for the inhibition of sorbitol dehydrogenase, because these two groups in the active SDI-2 can complex with Zn, which is located within a sterically constrained pocket of the sorbitol dehydrogenase protein (9). 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2,6-dimethoxypyrimidine (SRA-1), is an analog in which the 2-methyl group in the 2-position of the pyrimidine ring has been replaced with a methoxy group.…”

Cloning and expression of the sorbitol dehydrogenase gene during embryonic development and temperature stress in Artemia sinica

“…The identification of the prototypical SDI CP-166,572 by Geissen (Geissen et al, 1994) made it possible for more potent SDIs to be synthesized (Chu-Moyer et al, 2002). In addition, this discovery led to the proposal that SDH could be inhibited by directly chelating the catalytic zinc (Mylari et al, 2001). The prodrug SDI-157 increases the activity of CP-166,572 by inducing a chemical change in its pyrimidine ring (Pauly et al, 2003).…”