title: Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues.
abstract: Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).
authors.affiliation: Dupont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. George.V.DeLucca@usa.dupont.com
authors.forename: G V
authors.initials: GV
authors.lastname: De Lucca
authors.forename: U T
authors.initials: UT
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.forename: B
authors.initials: B
authors.lastname: Cordova
authors.forename: R M
authors.initials: RM
authors.lastname: Klabe
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: G N
authors.initials: GN
authors.lastname: Lam
authors.forename: M R
authors.initials: MR
authors.lastname: Wright
authors.forename: K A
authors.initials: KA
authors.lastname: Logue
authors.forename: S
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: S S
authors.initials: SS
authors.lastname: Ko
authors.forename: G L
authors.initials: GL
authors.lastname: Trainor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015195:Drug Design; D004352:Drug Resistance, Microbial; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D012367:RNA, Viral / Q000096:biosynthesis; D019438:Ritonavir / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D001381:Azepines; D017320:HIV Protease Inhibitors; D007191:Indazoles; D012367:RNA, Viral; D014508:Urea; C085816:DMP 323; D019438:Ritonavir; C099851:DMP 450