title: Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors.
abstract: The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of Ki to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.
authors.affiliation: DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0500, USA. George.V.DeLucca@dupontpharma.com
authors.forename: G V
authors.initials: GV
authors.lastname: De Lucca
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.forename: I
authors.initials: I
authors.lastname: De Lucca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D012367:RNA, Viral