- 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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- USE OF ETHYNYL ALANINE AMINO DIOL COMPOUNDS FOR TREAMENT OF OPHTHALMIC DISORDERS
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Compounds characterized generally as ethynyl alanine amino diol derivatives are useful as renin inhibitors for the treatment of ophthalmic disorders. Compounds of particular interest are those of Formula I STR1 wherein A is selected from CO and SO 2 where
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- Enantioselective synthesis of the (syn,anti)-1-amino-2,3-diol subunit of renin inhibition by reaction of β-lactams with a Grignard reagent
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A new approach to the BOC-protected amino diol 1a via the opening of 3,4-cis-disubstituted β-lactam 3 with isobutylmagnesium chloride is described. Nonracemic β-lactam 3 could be obtained by enzymatic resolution of the 3-acetoxy-β-lactam 4 or from a chira
- Spero,Kapadia,Farina
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p. 4543 - 4546
(2007/10/02)
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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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- 3-AZABICYCLO[3.2.1]-NONANYL-TERMINATED NON-PIPTIDYL ALPHA-SUCCINAMIDOACYL AMINODIOLS AS ANTI-HYPERTENSIVE AGENTS
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Non-peptidyl compounds characterized generally as α-succinamidoacyl aminodiols having a 3-azabicyclo[3.2.2]-nonanyl-type group at the N-terminus are useful as renin inhibitors for the treatment of hypertension.
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- Diastereoselectivity in the osmium-catalyzed dihydroxylation of allylic amides and carbamates
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The stereochemistry of the osmium-catalyzed dihydroxylation of a series of chiral allylic amides and carbamates has been studied. The diastereoselectivity of these reactions was found to be dependent upon the solvent and the nitrogen protecting group as w
- Krysan,Rockway,Haight
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p. 625 - 632
(2007/10/02)
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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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- Dipeptide Isosteres. 1. Synthesis of Dihydroxyethylene Dipeptide Isosteres via Diastereoselective Additions of Alkyllithium Reagents to N,N-Dimethylhydrazones. Preparation of Renin and HIV-1 Protease Inhibitor Transition-State Mimics
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The amino and diamino dihydroxyethylene dipeptide isosteres 19a,b and 23 are important intermediates for the preparation of inhibitors of human renin and HIV-1 protease, respectively.A general synthetic strategy was developed to access both dipeptide isos
- Baker, William R.,Condon, Stephen L.
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p. 3277 - 3284
(2007/10/02)
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- A practical synthesis of the dihydroxyethylene dipeptide isostere, (2S, 3R, 4S) 2-[(tert-butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane, from D-isoascorbic acid
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The N-Boc dihydroxyethylene dipeptide isostere 7 and its N-Boc 3-(thiazol-4-yl)alanyl derivative 8 were synthesized, without purification of intermediates, from (4S,5R)-2,2-dimethyl-4-(2-methylpropyl)-5-hydroxymethyl-1,3-dioxolane (3b), in 24 and 32% over
- Baker, William R.,Condon, Stephen L.
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p. 1581 - 1584
(2007/10/02)
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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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- PEPTIDYL BETA-AMINOACYL AMINODIOL CARBAMATES AS ANTI-HYPERTENSIVE AGENTS
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Non-peptidyl compounds characterized generally as β-aminoacyl aminodiol carbamates are useful as renin inhibitors for the treatment of hypertension.
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- Novel synthesis of three types of C-terminal components of renin inhibitors from unnatural (2S,3S)-tartaric acid
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The addition reaction of cyclohexylmethylmagnesium bromide with the imine prepared from unnatural (2S,3S)-tartaric acid was found to proceed in a highly stereoselective manner in the presence of cerium(III) chloride. A chelation-controlled mechanism could
- Kobayashi,Matsumoto,Takemoto,Nakatani,Ito,Kamijo,Harada,Terashima
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p. 2550 - 2555
(2007/10/02)
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- Novel Synthesis of (2S,3R,4S)-4-Amino-5-cyclohexyl-1-morpholino-2,3-pentanediol and (2S,3R,4S)-2-Amino-1-cyclohexyl-6-methyl-3,4-heptandiol, the C-Terminal Components of Renin Inhibitors
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The title synthesis could be accomplished in a highly stereo-and regioselective manner by employing epoxide formation with inversion of configuration followed by epoxide opening with a nucleophile.
- Kobayashi, Yuko,Nakatani, Kazuhiko,Ito, Yoshio,Terashima, Shiro
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p. 1709 - 1710
(2007/10/02)
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- Poly(aminoalkyl)aminocarbonyl aminodiol amino acid derivatives as anti-hypertensive agents
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Non-peptidyl compounds characterized generally as poly(aminoalkyl)aminocarbonyl aminodiol derivatives of amino acids are useful as renin inhibitors for the treatment of hypertension.
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- PEPTIDYL ALPHA-AMINOACYL AMINODIOL CARBAMATES AS ANTI-HYPERTENSIVE AGENTS
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Non-peptidyl compounds characterized generally as aminoacyl aminodiol carbamates are useful as renin inhibitors for the treatment of hypertension.
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- ALPHA-AMINOACYL BETA-AMINOACYL AMINODIOLS AS ANTI-HYPERTENSIVE AGENTS
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Compounds characterized generally as α-aminoacyl β-aminoactyl aminodiols are useful as renin inhibitors for the treatment of hypertension.
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- Aminoalkylaminocarbonyl aminodiol amino acid derivatives as antihypertensive agents
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Non-peptidyl compounds characterized generally as aminoalkylaminocarbonyl aminodiol derivatives of amino acids are useful as renin inhibitors for the treatment of hypertension.
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- Ethereal N-terminal aminodiol amino acid derivatives as anti-hypertensive agents
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Non-peptidyl compounds characterized generally as ethereal N-terminal aminodiol derivatives of amino acids are useful as renin inhibitors for the treatment of hypertension.
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- Renin Inhibitors. Dipeptide Analogues of Angiotensinogen Utilizing a Dihydroxyethylene Transition-State Mimic at the Scissile Bond To Impart Greater Inhibitory Potency
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The synthesis of diol-containing inhibitors has revealed that a simple vicinal diol functionality corresponding to the scissile Leu-Val bond in human angiotensinogen is capable of imparting inhibitory activity at a comparable or higher level than either the corresponding aldehyde or hydroxymethyl functionality (compare inhibitors 2a-c or 3a-c).This finding has lead to the further optimization of a series of small transition-state analogue inhibitors by the inclusion of a second hydroxyl group in the Leu-Val surrogate to give compounds that inhibited human renin in the 200-700-pM range (e.g. 43, 45, 63, 66).The magnitude of effect of the second hydroxyl group on potency is not only dictated by the absolute stereochemistry of the diol but also by the side chain of the P1 residue.Molecular modeling of the diol-containing inhibitors suggests that one of the hydroxyl groups hydrogen bonds to Asp 32 and Asp 215, while the second hydrogen bonds to Asp 215.These diol inhibitors are extremely selective for human renin over the related enzymes cathepsin D, pepsin, and gastricsin.At high concentrations, compounds containing a leucine or phenylalanine rather than a histidine at the P2 position gave only minor amounts of inhibition of the other enzymes.Inhibitor 43 suppressed plasma renin activity completely and lowered mean blood pressure in monkeys after both intravenous and intraduodenal administration, but the blood pressure drop lasted les than 1 h.Monitoring the blood levels of 43 by enzyme inhibition assay after intraduodenal administration to monkeys or oral administration to rats revealed low absorption and rapid clearance.While intratracheal administration to dogs gave approximately 50percent bioavailability, rapid clearance was still a problem.After examination of inhibitor 45 in a sensitive primate model in which monkeys were rendered both hypertensive and hyperreninemic, the effects on lowering systolic but not diastolic pressure were apparent even after 22 h postdosing.Details on the synthesis, in vitro structure-activity relationships, molecular modeling, in vivo activity, and metabolism of these inhibitors are described.
- Luly, Jay R.,BaMaung, Nwe,Soderquist, Jeff,Fung, Anthony K. L.,Stein, Herman,et al.
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p. 2264 - 2276
(2007/10/02)
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