title: Quinazolineacetic acids and related analogues as aldose reductase inhibitors.
abstract: A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14,15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.
authors.affiliation: Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
authors.forename: M S
authors.initials: MS
authors.lastname: Malamas
authors.forename: J
authors.initials: J
authors.lastname: Millen
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D007202:Indicators and Reagents; D007908:Lens, Crystalline / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D007202:Indicators and Reagents; D011799:Quinazolines; D000449:Aldehyde Reductase