title: The development of cyclic sulfolanes as novel and high-affinity P2 ligands for HIV-1 protease inhibitors.
abstract: Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the S2-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as P2 ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in vitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2-isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (IC50 3.5 nM, CIC95 50 +/- 14 nM) of comparable in vitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the P1' decahydroisoquinoline derivative.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: A K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: C
authors.initials: C
authors.lastname: Culberson
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: S P
authors.initials: SP
authors.lastname: McKee
authors.forename: P M
authors.initials: PM
authors.lastname: Munson
authors.forename: T T
authors.initials: TT
authors.lastname: Duong
authors.forename: A M
authors.initials: AM
authors.lastname: Smith
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D001665:Binding Sites; D003500:Cyclization; D003517:Cyclopentanes / Q000737:chemistry; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D019258:Saquinavir; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D003517:Cyclopentanes; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; C086909:N-tert-butyldecahydro-2-(2-hydroxy-4-phenyl-3-((((2'-(1-methylethyl)-1',1'-dioxotetrahydrothiophene-3'-yl)oxy)carbonyl)amino)butyl)isoquinoline-3-carboxamide; C086908:N-tert-butyloctahydro-1H-pyrindene-3-carboxamide; D010880:Piperidines; D011804:Quinolines; D013876:Thiophenes; D016333:HIV Protease; D019258:Saquinavir