title: Epsilon substituted lysinol derivatives as HIV-1 protease inhibitors.
abstract: A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-L-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. kristen_jones@merck.com
authors.forename: Kristen L G
authors.initials: KL
authors.lastname: Jones
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Hua-Poo
authors.initials: HP
authors.lastname: Su
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.forename: Sinoeun
authors.initials: S
authors.lastname: Touch
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DiStefano
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
mesh_terms: D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008239:Lysine / Q000031:analogs & derivatives*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008239:Lysine