Orally‐Effective, Long‐Acting Sorbitol Dehydrogenase Inhibitors: Synthesis, Structure‐Activity Relationships, And In Vivo Evaluations Of Novel Heterocycle‐Substituted Piperazino‐Pyrimidines

Abstract

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N‐dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half‐lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1‐2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.

Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium

“…In the second group of hearts, after the equilibration period of 30 min, hearts (n=6) were perfused with modified Krebs-Henseleit buffer containing 200 nM of SDH inhibitor (CP-470,711) starting 10 min before ischemia and contining throughout ischemia and reperfusion. CP-470,711 was synthesized at the Department of Medicinal Chemistry at Pfizer Global Research and Development, as published earlier (20). The inhibitor concentration of 200 nM was chosen based on dose-response studies ( Table 1).…”

“…The inhibitor concentration of 200 nM was chosen based on dose-response studies ( Table 1). This inhibitor is highly selective for SDH and is inactive against most dehydrogenases including lactate dehydrogenase, alcohol dehydrogenase, fructose dehydrogenase, and glucose 6-phosphate dehydrogenase (20).…”

Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of a Novel Sorbitol Dehydrogenase Inhibitor in Healthy Participants

“…2,8 For example, in diabetic rats, inhibition of SDH has been reported to elevate tissue sorbitol and lower tissue fructose, while attenuating vascular dysfunction and protecting nerve function and lowering urinary albumin excretion. [9][10][11] Treatment with a sorbitol dehydrogenase inhibitor (SDI) had no detrimental effect on nerve conduction velocity in normal rats 9,12 or on adenine dinucleotide redox status, energy states, lipid aldehyde, or reduced glutathione concentrations in the nerve of normal rats. 13 However, SDI treatment of streptozotocin-diabetic rats, while having no 12 or a positive protective 10 effect on nerve conduction velocity (NCV), caused a slight acceleration of cataract formation, 9 an enhancement of neuroaxonal dystrophy (NAD), 8,14 and an exacerbation of lens and nerve glutathione loss and aldehyde accumulation.…”

“…Furthermore, the evidence indicates that metabolic flux through the polyol pathway, rather than tissue concentration of sorbitol, is the predominant polyol pathway‐linked pathogenic factor in diabetic microvascular complications 2 , 8 . For example, in diabetic rats, inhibition of SDH has been reported to elevate tissue sorbitol and lower tissue fructose, while attenuating vascular dysfunction and protecting nerve function and lowering urinary albumin excretion 9 – 11 . Treatment with a sorbitol dehydrogenase inhibitor (SDI) had no detrimental effect on nerve conduction velocity in normal rats 9 , 12 or on adenine dinucleotide redox status, energy states, lipid aldehyde, or reduced glutathione concentrations in the nerve of normal rats 13 .…”

Cobalt Hydride Oxidase Catalysis Enabled Hydroamination of Unactivated Olefins

“…Specifically, we targeted α-branched amine derivatives, in particular those bearing a methyl substituent, which play crucial roles in determining the potency and/or selectivity of numerous drug candidates (Figure 1c). [10][11][12][13][14] A straightforward strategy to construct these structures is offered by catalytic Markovnikov-selective addition of an amine across an olefin (Figure 1d). Despite of considerable advances in this field over the past twenty years, challenges remain in the reactions of unactivated alkenes, especially in an intermolecular setting.…”