The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin.
Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.
Yamaguchi
Yasuchika
Y
Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki 859-3298, Japan.
Menear
Keith
K
Cohen
Nissim-Claude
NC
Mah
Robert
R
Cumin
Frédéric
F
Schnell
Christian
C
Wood
Jeanette M
JM
Maibaum
Jürgen
J
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002144:Callithrix; D005030:Ethylenes / Q000737:chemistry*; D005650:Fumarates / Q000737:chemistry*; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012083:Renin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D001549:Benzamides; D005030:Ethylenes; D005650:Fumarates; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren; C067254:hydroxyethylene