Epsilon substituted lysinol derivatives as HIV-1 protease inhibitors.
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.
Jones
Kristen L G
KL
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. kristen_jones@merck.com
Holloway
M Katharine
MK
Su
Hua-Poo
HP
Carroll
Steven S
SS
Burlein
Christine
C
Touch
Sinoeun
S
DiStefano
Daniel J
DJ
Sanchez
Rosa I
RI
Williams
Theresa M
TM
Vacca
Joseph P
JP
Coburn
Craig A
CA
D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008239:Lysine / Q000031:analogs & derivatives*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D008239:Lysine