Design and synthesis of renin inhibitors: incorporation of transition-state isostere side chains that span from the S1 to the S3 binding pockets and examination of P3-modified renin inhibitors.
A series of renin inhibitors were designed to examine the topography of the contiguous binding pocket of renin that is normally occupied by the P1 and P3 side chains. Molecular modeling suggested that extending the P1 hydrophobic side chain into the adjacent hydrophobic S3 enzyme pocket was feasible. Novel transition state isosteres with modified P1-->P3 side chains were synthesized and provided enhanced binding affinity when incorporated into renin inhibitors in which the P3 Phe was substituted by Gly. In a complementary approach, the binding affinities of a variety of P3-P4-modified peptidomimetic renin inhibitors that lacked substantial hydrophobic side chains at these sites were measured.
Plummer
M S
MS
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48106, USA.
Shahripour
A
A
Kaltenbronn
J S
JS
Lunney
E A
EA
Steinbaugh
B A
BA
Hamby
J M
JM
Hamilton
H W
HW
Sawyer
T K
TK
Humblet
C
C
Doherty
A M
AM
D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D000882:Haplorhini; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D015394:Molecular Structure; D010649:Phenylalanine / Q000378:metabolism; D012083:Renin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D006536:Heptanes; D010649:Phenylalanine; D012083:Renin; D000092502:Renin Inhibitors