1. N-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid aldose reductase inhibitors derived from isoquinoline-1,3-diones. 2
M S Malamas, T C Hohman J Med Chem. 1994 Jun 24;37(13):2059-70. doi: 10.1021/jm00039a018.
The isoquinoline-1,3-dione framework featured in our clinical candidate (1) and its congener was used as the template in the design of several new series of aldose reductase inhibitors (ARIs). These series included N'-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid analogues. Compounds within these series were evaluated in vitro for their ability to inhibit glyceraldehyde reduction by bovine lens aldose reductase and in vivo by their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. The N'-amino- and N'-alkyl-substituted spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)- tetrones 6 exhibited high oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. Similar results were observed for the closely related spiropyridazines 8. Both of these groups are also considered to be prodrugs since they exhibited good oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. In contrast, the isoquinoline-1,3-dione acetic acids 9 exhibited very high intrinsic activity for the aldose reductase enzyme, although minimal or no in vivo activity. The absence of in vivo activity for some of these compounds may be due to poor tissue penetration. In support of this suggestion, the more lipophilic acetyl alkyl carbamate derivatives of these isoquinoline-1,3-dione acetic acids, exhibited enhanced oral potency. The spiroazetidines 7 exhibited good activity for the aldoe reductase enzyme in both the in vitro and in vivo assays. The findings of this study demonstrate the utility of the isoquinoline-1,3-dione framework, as a versatile template for the design of divese series of potent ARIs.
2. Novel spirosuccinimide aldose reductase inhibitors derived from isoquinoline-1,3-diones: 2-[(4-bromo-2-fluorophenyl)methyl]-6- fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone and congeners. 1
M S Malamas, T C Hohman, J Millen J Med Chem. 1994 Jun 24;37(13):2043-58. doi: 10.1021/jm00039a017.
The high concentrations of plasma glucose formed during diabetic hyperglycemia rapidly translate into high levels of glucose in tissues where glucose uptake is independent of insulin. In these tissues that include the lens, retina, nerve, and kidney, this excess glucose enters the sorbitol (polyol) pathway. The first enzyme in this pathway, aldose reductase, reduces glucose to sorbitol. The diabetes-induced increased flux of glucose through the polyol pathway is believed to play an important role in the development of certain chronic complications of diabetes mellitus. Compounds that inhibit aldose reductase activity and block the flux of glucose through the polyol pathway prevent the development of neuropathy and nephropathy in diabetic animals and interrupt the progression of neuropathy in diabetic patients. Here we describe the preparation and characterization of novel aldose reductase inhibitors. These spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'-(2H)-tetrones, based on the isoquinoline-1,3-dione framework, were evaluated in vitro for their ability to inhibit glyceraldehyde reduction, using a partially purified bovine lens aldose reductase preparation, and in vivo for their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. Substitution at the N-2 position of the isoquinoline-1,3-dione framework with diverse structural substituents (i.e., aralkyl, benzothiazolylmethyl, methyl) produced several excellent series of ARIs. Optimization of these new series of spirosuccinimides through structure-activity relationship (SAR) studies, including analogy from other drug series (ponalrestat, zopolrestat), led to the design of the clinical candidate 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H ),3'- pyrrolidine]-1,2',3,5'(2H)-tetrone (41). Compound 41 exhibited exceptional oral potency in two animal models of diabetic complications, the 14-day galactose-fed and streptozocin-induced diabetic rats, with ED50 values for the sciatic nerve of 0.1 and 0.09 mg/kg/day, respectively. Both enantiomeric forms of 41 exhibited similar inhibitory activity in both in vitro and in vivo assays possibly due to their rapid interconversion. In an ex vivo experiment, the pharmacodynamic effect of 41 in the plasma of rats and dogs, after a single dose, appeared to be comparable to that of tolrestat.
3. Orally active aldose reductase inhibitors derived from bioisosteric substitutions on tolrestat
J Wrobel, J Millen, J Sredy, A Dietrich, J M Kelly, B J Gorham, K Sestanj J Med Chem. 1989 Nov;32(11):2493-500. doi: 10.1021/jm00131a012.
A series of aldose reductase inhibitors was prepared in which structural modifications were made to three positions of the potent, orally active inhibitor tolrestat (1), namely, the 6-methoxy substituent, thioamide sulfur, and the N-methyl moiety. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated rat sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Bioisosteric replacement of the 6-methoxy group of 1 with a methylthio substituent gave 5, and replacement of the thioamide substituent of 1 with a cyanoamidine gave 7. Both 5 and 7 retained high in vitro potency but were less potent in vivo than 1. Replacement of the tolrestat N-methyl group by a carbomethoxy moiety gave 10 and led to a substantial reduction in activity in each of the three assays employed. However, this same structural modification on oxo-tolrestat (2) led to 11 and resulted in an enhancement of the intrinsic activity and a comparable in vivo potency. The isolated nerve data suggest that some compounds in these series do not readily penetrate into peripheral nerves, and this presumably is a factor in their lack of oral activity.
