Design and synthesis of potent macrocyclic renin inhibitors.
Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the K(i) and the human plasma renin activity (HPRA)IC(50) was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (K(i) = 3.3 nM and HPRA IC(50) = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (K(i) = 34 nM and HPRA IC(50) = 56 nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin.
Medivir AB, PO Box 1086, SE-14122 Huddinge, Sweden. christian.sund@medivir.se
Christian
C
Sund
Oscar
O
Belda
Daniel
D
Wiktelius
Christer
C
Sahlberg
Lotta
L
Vrang
Susanne
S
Sedig
Elizabeth
E
Hamelink
Ian
I
Henderson
Tatiana
T
Agback
Katarina
K
Jansson
Neera
N
Borkakoti
Dean
D
Derbyshire
Anders
A
Eneroth
Bertil
B
Samuelsson
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012083:Renin / Q000378:metabolism; D000092502:Renin Inhibitors
D016282:Aspartic Acid Endopeptidases; D002402:Cathepsin D; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors