Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors
A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds...
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| Veröffentlicht in: | Journal of medicinal chemistry 1992-07, Vol.35 (14), p.2562-2572 |
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| container_end_page | 2572 |
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| container_issue | 14 |
| container_start_page | 2562 |
| container_title | Journal of medicinal chemistry |
| container_volume | 35 |
| creator | Patt, William C Hamilton, Harriet W Taylor, Michael D Ryan, Michael J Taylor, David G Connolly, Cleo J. C Doherty, Annette M Klutchko, Sylvester R Sircar, Ila |
| description | A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model. |
| doi_str_mv | 10.1021/jm00092a006 |
| format | Article |
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C</creatorcontrib><creatorcontrib>Doherty, Annette M</creatorcontrib><creatorcontrib>Klutchko, Sylvester R</creatorcontrib><creatorcontrib>Sircar, Ila</creatorcontrib><title>Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.</description><subject>Animals</subject><subject>Blood Pressure - drug effects</subject><subject>Cathepsin D - antagonists & inhibitors</subject><subject>Chemistry</subject><subject>Dogs</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Stability</subject><subject>Exact sciences and technology</subject><subject>Humans</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Organic chemistry</subject><subject>Peptides</subject><subject>Preparations and properties</subject><subject>Rats</subject><subject>Renin - antagonists & inhibitors</subject><subject>Renin - metabolism</subject><subject>Species Specificity</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1vEzEQxS1EVULhxBlpDwgOyDD-zh5RxUelqCA1XLEmjpc47K5T24to_3pcNiocOL2R3m-eZh4hzxi8YcDZ2_0AAC1HAP2ALJjiQOUS5EOyAOCccs3FI_I4533FBOPilJwyLRQosyDfrkqaXJmSp-hK-BnKTZN8jyXEMe_CITexa7DJPgX_Z-YUhzBGKmnZBbyNvacujgXDGMbvdbVKE8Zd2IQSU35CTjrss3961DPy9cP79fknuvr88eL83YqilG2hLXZ8IxwquXEKt7rD-g13Svh6sFYGnJSMeaeFkQyUdswJAKb5tmv9VmpxRl7OuYcUryefix1Cdr7vcfRxytYIWBpueAVfz6BLMefkO3tIYcB0YxnYuzbtP21W-vkxdtoMfvuXneur_oujj9lh3yUcXcj3mJJ6CUpUjM5YyMX_urcx_bDaCKPs-suVXYuVWa7bS3sX-2rm0WW7j1Maa3f_PfA3AfeX1w</recordid><startdate>19920701</startdate><enddate>19920701</enddate><creator>Patt, William C</creator><creator>Hamilton, Harriet W</creator><creator>Taylor, Michael D</creator><creator>Ryan, Michael J</creator><creator>Taylor, David G</creator><creator>Connolly, Cleo J. 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| ispartof | Journal of medicinal chemistry, 1992-07, Vol.35 (14), p.2562-2572 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Blood Pressure - drug effects Cathepsin D - antagonists & inhibitors Chemistry Dogs Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Stability Exact sciences and technology Humans Macaca fascicularis Male Organic chemistry Peptides Preparations and properties Rats Renin - antagonists & inhibitors Renin - metabolism Species Specificity Structure-Activity Relationship Thiazoles - chemistry Thiazoles - pharmacology |
| title | Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors |
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