- 1-HETEROCYCLYLAMINO-2-HYDROXY-3-AMINO-ω-ARYLALKANES
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1-Heterocyclylamino-2-hydroxy-3-amino-?-arylalkanes of formula (I) and the salts thereof have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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- Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl- octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin
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The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2′ modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
- G?schke, Richard,Stutz, Stefan,Rasetti, Vittorio,Cohen, Nissim-Claude,Rahuel, Joseph,Rigollier, Pascal,Baum, Hans-Peter,Forgiarini, Peter,Schnell, Christian R.,Wagner, Trixie,Gruetter, Markus G.,Fuhrer, Walter,Schilling, Walter,Cumin, Frédéric,Wood, Jeanette M.,Maibaum, Jürgen
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p. 4818 - 4831
(2008/03/13)
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- 1-ACYLAMINO-2-HYDROXY-3-AMINO-W-ARYLALKANES AS RENIN INHIBITORS
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1-Acylamino-2-hydroxy-3-amino-ω-arylalkanes of formula I. and the salts thereof, have renin-inhibiting properties and can be used as antihypertensive, medicinally active ingredients.
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Page/Page column 79; 81
(2008/06/13)
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- Practical synthesis of an orally active renin inhibitor aliskiren
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A convergent synthesis of aliskiren was accomplished via the use of Segment AB as the key intermediate, which was prepared via the coupling of the Grignard reagent derived from Segment B with Segment A, followed by subsequent oxidative lactonization.
- Dong, Hua,Zhang, Zhi-Liu,Huang, Jia-Hui,Ma, Rujian,Chen, Shu-Hui,Li, Ge
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p. 6337 - 6340
(2007/10/03)
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- METHODS OF TREATING ALZHEIMER'S DISEASE USING ARYL ALKANOIC ACID AMIDES
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Disclosed are methods for treating Alzheimer’s disease, and other diseases, and/or inhibiting beta-secretase enzyme, and/or inhibiting deposition of A beta peptide in a mammal, by use of compounds of formula 1 (1) wherein the variables R1-R8 and X are defined herein.
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Page 233-234
(2010/02/05)
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