Diethoxymethylphosphonites and phosphinates. Intermediates for thesynthesis of α,β- and X aminoalkylphosphonous acids

Dingwalla, J.G.; Ehrenfreund, Josef; Hall, Roger G.

doi:10.1016/s0040-4020(01)89240-1

Cited by 78 publications

(26 citation statements)

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“…Neither the method by Baylis et al [57] nor the most recently described preparation [58] were successful in our hands. Therefore, a third procedure [59,60] was attempted and proved to be successful. Thus, reaction of ethyl (diethoxymethyl)phosphinate [61,62] with 1,3,5-(diphenylmethyl)-hexahydro-s-triazine [57] followed by complete deprotection with concentrated aqueous HBr gave the desired compound 2 a.…”

Section: Resultsmentioning

confidence: 99%

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Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

et al. 1999

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The solid-phase synthesis of an array of different pseudopeptides containing a phosphinic glycine ± leucine moiety (-GY{P(O)OH-CH 2 }L-) [1] is described. The resulting pseudopeptides were shown to act as matrix metalloproteinase-9 (MMP-9) inhibitors. Starting from available materials, the protected amino acid isosters benzyloxycarbonyl aminomethylphosphinic acid (glycine analogue) and ethyl a-isobutylacrylate (leucine analogue) were synthesized and coupled with the bis(trimethylsilyl)phosphonite. Protective group interchange yielded a protected phosphinic dipeptide building block 1 ready for use in solid-phase peptide synthesis. Solid-phase peptide synthesis was performed with 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry on a polyethylene glycol polyamide (PEGA) support and the coupling of 1 (1.5 equiv) was carried out with standard activation. The P 4 ± P 2 and P 2 ' ± P 4 ' positions of the pseudopeptides were designed by analogy of the cleavage sequences of different natural extracellular matrix protein substrates with a synthetic peptide substrate of MMP-9. The crude peptides were obtained in high yield and purity as determined by RP-HPLC, and were characterized by electrospray mass spectrometry and amino acid analysis after purification. Enzyme kinetic investigations with MMP-9 of the purified peptide inhibitors showed K i values in the range from mm to nm.

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Section: Resultsmentioning

confidence: 99%

“…Aminomethylphosphinic acid (2 a): [78] Phosphinic acid 2 a was efficiently prepared analogous to a literature procedure [59] on a 300 mmol scale, although the pure amino acid could not be successfully precipitated with propylene oxide as previously reported.…”

Section: Resultsmentioning

confidence: 99%

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

et al. 1999

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“…All compounds except for compound 1 (Tocris, Bristol, UK) were synthesized at AstraZeneca R&D Mölndal or at Albany Molecular Research, Albany, NY. The synthetic procedures were according to those described in Dingwall et al . (1989) (compounds 2 and 18), Froestl et al .…”

Section: Methodsmentioning

confidence: 99%

Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABA_B receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation

Lehmann

Antonsson

Aurell-Holmberg

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEGastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABAB receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABAB receptors. To understand the structure-activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acids), and corresponding 3-aminopropyl(methyl)phosphinic acids, we have compared representatives of these classes in different in vitro and in vivo models. EXPERIMENTAL APPROACHThe compounds were characterized in terms of GABAB agonism in vitro. Binding to GATs and cellular uptake was done using rat brain membranes and slices respectively. TLOSR was measured in dogs, and CNS side effects were evaluated as hypothermia in mice and rats. KEY RESULTS3-Aminopropylphosphinic acids inhibited TLOSR with a superior therapeutic index compared to 3-aminopropyl(methyl)phosphinic acids. This difference was most likely due to differential GAT-mediated uptake into brain cells of the former but not latter. In agreement, 3-aminopropyl(methyl)phosphinic acids were much more potent in producing hypothermia in rats even when administered i.c.v. CONCLUSIONS AND IMPLICATIONSAn enhanced therapeutic window for 3-aminopropylphosphinic acids compared with 3-aminopropyl(methyl)phosphinic acids with respect to inhibition of TLOSR was observed and is probably mechanistically linked to neural cell uptake of the former but not latter group of compounds. These findings offer a platform for discovery of new GABAB receptor agonists for the treatment of reflux disease and other conditions where selective peripheral GABAB receptor agonism may afford therapeutic effects.

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“…We have previously reported 8,9 the synthesis of α-aminophosphinic acids R-PO 2 H 2 as analogs of the protein amino acids. Although the P O and P C bonds are 15-20% longer than the C O and C C bonds in the carboxylate group, the overlap of the key binding atoms is good.…”

Section: Bio-isosteric Replacements Of Carboxylic Acidsmentioning

confidence: 99%

The Role of Phosphorus in Crop Protection: Commercial and Experimental Weed Control Agents

Hall

2008

Phosphorus, Sulfur, and Silicon and the Related Elements

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Diethoxymethylphosphonites and phosphinates. Intermediates for thesynthesis of α,β- and X aminoalkylphosphonous acids

Cited by 78 publications

References 10 publications

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABA_B receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation

The Role of Phosphorus in Crop Protection: Commercial and Experimental Weed Control Agents

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Diethoxymethylphosphonites and phosphinates. Intermediates for thesynthesis of α,β- and X aminoalkylphosphonous acids

Cited by 78 publications

References 10 publications

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABAB receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation

The Role of Phosphorus in Crop Protection: Commercial and Experimental Weed Control Agents

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Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABA_B receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation