- An efficient process for the synthesis of renin inhibitor, ABT-517
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An efficient process for the preparation of renin inhibitor, ABT-517 is described. The process avoids solvent extractions or chromatographic purfications and is used on multi-kilogram scale.
- Singam, Pulla Reddy,Bradshaw, Curt W.,Menzia, Jerome A.,Narayanan,Rockway, Todd W.,Welch, Noel,Tien, Jien-Heh J.
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- A study on the "non-chelation controlled" organometallic addition to trans α,β-epoxy aldehydes - A straightforward stereoselective synthesis of the Abbot amino dihydroxyethylene dipeptide isoster
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A study of the organometallic addition to α,β-epoxy aldehydes in "non-chelation controlled" conditions is reported. The conditions able to give the best stereoselectivities are used to prepare the Abbott amino diol. Wiley-VCH Verlag GmbH, 69451 Weinheim,
- Righi, Giuliana,Ronconi, Silvia,Bonini, Carlo
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p. 1573 - 1577
(2007/10/03)
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- Practical synthesis of Abbott amino-diol: A core unit of the potent renin inhibitor Zankiren
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Abbott amino-diol (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl heptane-3,4- diol 1, a main structural constituent of the orally active renin inhibitor Zankiren has been synthesized using Sharpless asymmetric aminohydroxylation as the key step.
- Chandrasekhar,Mohapatra, Suchismita,Yadav
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p. 4763 - 4768
(2007/10/03)
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- A diastereoselective synthesis of (2S, 3R, 4S)-2-amino-1-cyclohexyl-6-methylheptane-3,4-diol, the Abbott aminodiol
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An efficient asymmetric synthesis of the Abbott aminodiol, 1, is described beginning with the readily-available starting material, L-phenylalanine.
- Alexander,Liotta
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p. 1961 - 1964
(2007/10/03)
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- Time-resolved ligand exchange reactions: Kinetic models for competitive inhibitors with recombinant human renin
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The on and off rate constants (k(on) and k(off)) were determined for a series of peptidomimetic, competitive inhibitors of human renin using a novel binding assay. The method entails analyzing a pair of ligand exchange reactions in which a dansylated inhi
- Morelock,Pargellis,Graham,Lamarre,Jung
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p. 1751 - 1761
(2007/10/03)
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- ALKYLAMINOALKYL-TERMINATED SULFIDE/SULFONYL-CONTAINING PROPARGYL AMINO-DIOL COMPOUNDS FOR TREATMENT OF HYPERTENSION
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Compounds characterized generally as alkylaminoalkyl-terminated sulfide/sulfonyl-containing propargyl amino-diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula II: STR1 wherein q is two or three; wherein r is zero or two; wherein R 2 is selected from hydrido, methyl, ethyl and phenyl; wherein R 3 is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R. sup.5 is propargyl or a propargyl containing moiety; wherein R. sup.7 is cyclohexylmethyl; wherein R 8 is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; and wherein each of R. sup.12 and R 13 is a group independently selected from methyl, ethyl and isopropyl; or a pharmaceutically-acceptable salt thereof.
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- ETHYNYL ALANINE AMINO DIOL COMPOUNDS HAVING A PIPERAZINYL-TERMINATED GROUP OR A PIPERAZINYL-ALKYLAMINO-TERMINATED GROUP FOR TREATMENT OF HYPERTENSION
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Compounds characterized generally as ethynyl alanine amino diol compounds having a piperazinyl-terminated or a piperazinyl-alkylamino-terminated group and derivatives thereof are useful as renin inhibitors for the treatment of hypertension. Compounds of p
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- Imidazolyl/benzimidazolyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension
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Compounds characterized generally as imidazolyl/benzimidazolyl-terminated alkylamino ethynyl alanine amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of Formula I STR1 wher
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- CYCLOPROPYL-ALANINE ARYL/ALKYLSULFIDE/SULFONYL-TERMINATED AMINO-DIOL COMPOUNDS FOR TREATMENT OF HYPERTENSION
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Compounds characterized generally as cyclopropyl alanine aryl/alkylsulfide/sulfonyl-terminated amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of the formula STR1 wherein
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- Potent and Selective Inhibitors of an Aspartyl Protease-like Endothelin Converting Enzyme Identified in Rat Lung
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Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed.Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series.Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity.Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity.Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D.Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing.Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.
- Shiosaki, Kazumi,Tasker, Andrew S.,Sullivan, Gerard M.,Sorensen, Bryan K.,Geldern, Thomas W. von,et al.
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p. 468 - 478
(2007/10/02)
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- Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides
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A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N- terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 ± 4%) is the highest reported for any peptidic renin inhibitor.
- Rosenberg,Spina,Woods,Polakowski,Martin,Yao,Stein,Cohen,Barlow,Egan,Tricarico,Baker,Kleinert
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p. 449 - 459
(2007/10/02)
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- ENCAPSULATED RENIN INHIBITOR COMPOSITION
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A pharmaceutical composition comprising a solution of a tenin inhibitor of the formula: STR1 wherein R 1 is 4-piperazinyl, 1-methyl-4-piperazinyl, 1-methyl-1-oxo-4-piperazinyl, 2-oxo-4-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl or 1-methyl-4-homopiperazinyl; R 2 is benzyl, p-methoxybenzyl, 2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl;R 3 is 4-thiazolyl, 2-amino-4-thiazolyl, 2-thiazolyl, 5-thiazolyl, 1-pyrazolyl, 3-pyrazolyl, 1-imidazolyl, n-propyl, isopropyl, CH 3 S--or CH 3 SCH 2--;R 4 is loweralkyl or cyclopropyl;R 5 is hydrogen or loweralkyl; andX is CH 2 or NH; or a pharmaceutically acceptable salt, ester or prodrug thereof in a pharmaceutically acceptable solvent, said solution being encapsulated in a soft elastic gelatin capsule.
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- A VERSATILE AND STEREOSPECIFIC SYNTHESIS OF A DIHYDROXYETHYLENE DIPEPTIDE ISOSTERE OF RENIN INHIBITORS FROM D-RIBOSE
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(2S,3R,4S)-2-Amino-1-cyclohexyl-6-methylheptane-3,4-diol, a dihydroxyethylene dipeptide isostere for renin inhibitors, was synthesized from D-ribose stereospecifically.This method can be readily adapted to other dihydroxyethylene isosteres.
- Chan, Ming Fai,Hsiao, Chi-Nung
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p. 3567 - 3570
(2007/10/02)
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- 1,2,3-Trisubstituted Cyclopropanes as Conformationally Restricted Peptide Isosteres: Application to the Design and Synthesis of Novel Renin Inhibitors
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The 1,2,3-trisubstituted cyclopropanes 6 and 7 are the first members of a novel class of isosteric replacements for peptide linkages that are more generally represented by the dipeptide mimics 2 and 3.These unique peptide surrogates are specifically desig
- Martin, Stephen F.,Austin, Richard E.,Oalmann, Christopher J.,Baker, William R.,Condon, Stephen L.,et al.
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p. 1710 - 1721
(2007/10/02)
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- Psoriasis treatment
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The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treatment of psoriasis.
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- PEPTIDYL AMINODIOL RENIN INHIBITORS
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A renin inhibiting compound having an aminodiol functional group is useful for treating hypertension, congestive heart failure and glaucoma and inhibits retroviral protease.
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- A Versatile, Efficient Synthesis of (-)-(2S, 3R, 4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane, The Abbott Pseudodipeptidyl Insert
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An economic construction (6 steps, 36percent yield) of a valuable peptide analog subunit, the Abbott pseudodipeptidyl insert (-)-(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (1), has been developed.
- Wood, John L.,Jones, David R.,Hirschmann, Ralph,Smith, Amos B.
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p. 6329 - 6330
(2007/10/02)
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- Potent, Low Molecular Weight Renin Inhibitors Containing a C-Terminal Heterocycle: Hydrogen Bonding at the Active Site
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A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl.Molecular modeling suggests that the heterocyclic oxygen hydrogen
- Rosenberg, Saul H.,Dellaria, Joseph F.,Kempf, Dale J.,Hutchins, Charles W.,Woods, Keith W.,et al.
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p. 1582 - 1590
(2007/10/02)
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- Renin inhibitory peptides containing suleptanic acid or derivatives thereof
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The present invention provides novel renin-inhibiting peptides having a non-cleavable transition state insert corresponding to the 10,11- position of the renin substrate (angiotensinogen) and having a suleptanic acid moiety or derivatives thereof of the formula L1 at the N-terminus of the peptide. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renin dependent hyperaldosterism, other renin depen-dent cardiovascular disorders and ocular disorders. , Y103S-(CH2)n-N(R1)- q-
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- Renin inhibiting peptides with polar end groups
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The present invention provides novel renin-inhibiting peptides having a noncleavable transition state insert corresponding to the 10,11- position of the renin substrate (angiotensinogen) and a polyhydroxy-substituted alkyl moiety bonded directly through carbon or nitrogen to the N-terminus. Such inhibitors are useful for the diagnosis and control of renin-dependent hypertension and other related diseases.
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