title: P1-substituted symmetry-based human immunodeficiency virus protease inhibitors with potent antiviral activity against drug-resistant viruses.
abstract: Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.
authors: Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, United States. david.degoey@abbott.com
authors: David A
authors: DA
authors: Degoey
authors: David J
authors: DJ
authors: Grampovnik
authors: Hui-Ju
authors: HJ
authors: Chen
authors: William J
authors: WJ
authors: Flosi
authors: Larry L
authors: LL
authors: Klein
authors: Tatyana
authors: T
authors: Dekhtyar
authors: Vincent
authors: V
authors: Stoll
authors: Mulugeta
authors: M
authors: Mamo
authors: Akhteruzzaman
authors: A
authors: Molla
authors: Dale J
authors: DJ
authors: Kempf
mesh_terms: D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors