Disease relevance of Phosphinic acid

• Phosphinate analogs of D-, D-dipeptides: slow-binding inhibition and proteolysis protection of VanX, a D-, D-dipeptidase required for vancomycin resistance in Enterococcus faecium [1].
• We have also identified a phosphinate-containing substrate analog that inhibits both E. coli and A. aeolicus LpxC, suggesting that the LpxC reaction proceeds by a mechanism similar to that described for other zinc metalloamidases, like carboxypeptidase A and thermolysin [2].
• Like other retroviral proteases, the MMTV enzyme was active as a dimer, showed maximum activity at pH between 4 and 6, and could be inhibited by pepstatin A and a phosphinic acid derivative HIV-1 protease inhibitor [3].
• The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leukemia L1210 and P-388 in mice but less active than the previously synthesized, simpler phosphinate derivatives 2 and 3 [4].
• To target thrombosis in a new way, we have identified and optimized a phosphinic acid-containing inhibitor of CPB, EF6265 [(S)-7-amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino) propyl]hydroxyphosphinoyl]methyl]heptanoic acid] and determined both the pharmacological profile and pathophysiological role of CPB in rat thrombolysis [5].

High impact information on Phosphinic acid

• Partial proteolysis of VanX reveals two protease-sensitive loop regions that are protected by the intermediate analog phosphinate, indicating that they may be part of the VanX active site [1].
• The enzymatic activity of VanX was previously found to be inhibited by the phosphinate analogs of the proposed tetrahedral intermediate for hydrolysis of D-Ala-D-Ala [1].
• Recent developments include the usage of the cross-coupling reaction for preparation of phosphine ligands and the involvement of low molecular weight phosphinic acid derivatives for the synthesis of unsaturated phosphinic and phosphonic acid derivatives [6].
• Aldehyde and phosphinate analogs of glutathione and glutathionylspermidine: potent, selective binding inhibitors of the E. coli bifunctional glutathionylspermidine synthetase/amidase [7].
• RESULTS: Phosphinate and phosphonate dipeptide analogs (which, after phosphorylation by the enzyme, mimic intermediates in the ligation reaction) were prepared and evaluated as reversible inhibitors of the wild-type ligases DdlA and DdlB from Escherichia coli and of the mutant enzyme VanA [8].

Chemical compound and disease context of Phosphinic acid

• Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis [9].
• This study used a modified 4 x 4 factorial randomized, double-blind, placebo-controlled, parallel group design to study the efficacy of 17 different doses of fosinopril (Fos), a phosphinic acid derived ACE inhibitor, and hydrochlorothiazide (HCTZ) in 550 patients with mild to moderate hypertension [10].
• Studies on the biosynthesis of bialaphos (SF-1293) Part 3. Production of phosphinic acid derivatives, MP-103, MP-104 and MP-105, by a blocked mutant of Streptomyces hygroscopicus SF-1293 and their roles in the biosynthesis of bialaphos [11].
• To assess the utility of phosphinates as pretreatments against nerve agents, experiments were conducted to determine whether oximes can reactivate phosphinate-inhibited guinea pig acetylcholinesterase (AChE) and whether the toxicity of phosphinates is reduced by treatment with atropine and/or oxime [12].

Biological context of Phosphinic acid

• Similarly, the kinetics of inhibition by a slow-binding phosphinate inhibitor in the presence of ATP are most altered in the S281A mutant [13].
• Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid [14].
• The GABA(B) agonist baclofen inhibited NK1R internalization evoked by 100 Hz root stimulation (IC50 1.5 microM), whereas the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP-55845) increased NK1R internalization evoked by 1 Hz root stimulation (EC50 21 nM) [15].
• The compound was chemically derivatised in a two-step process (acylation of the amino group and esterification of the phosphinic acid) [16].
• Benzyl (or alkyl) phosphinomethylphenylalanine derivatives were prepared by alkylation of an amino acid P-H phosphinate [17].

Anatomical context of Phosphinic acid

• A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) approximately 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes [18].
• The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice [19].
• Kinetic constants for selected phosphonate and phosphinate inhibitors of fetal bovine serum acetylcholinesterase (FBS AChE; EC 3.1.1.7), bovine caudate nucleus AChE (BCN AChE), and eel AChE have been determined [20].

Associations of Phosphinic acid with other chemical compounds

• Phosphinic pseudopeptides (i.e., peptide isosteres with one peptide bond replaced by a phosphinic acid moiety) were analyzed and physicochemically characterized by capillary zone electrophoresis in the pH range of 1.1-3.2, employing phosphoric, phosphinic, oxalic and dichloroacetic acids as background electrolyte (BGE) constituents [21].
• Amino and hydroxyl moieties were introduced into the phosphinic acid portion of the lead molecule to interact with ammonium binding site in the active cleft of the enzyme [22].
• The phosphinate in vitro produced 98% inhibition of the labelling of the band-1 polypeptide, with only 26% inhibition of the band-2 polypeptide, under conditions sufficient to inhibit neurotoxic esterase totally [23].
• Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo [24].
• The global heat response as measured by isothermal titration calorimetry in acetonitrile, which was obtained from the interaction of five different but structurally closely related guanidinium hosts with three rigid phosphinate guests of decreasing accessibility of their binding sites, is correlated to provide a trend analysis [25].

Gene context of Phosphinic acid

• Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1 [26].
• Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S2 pocket of these enzymes were designed [27].
• Three novel peptidomimetic phosphinate inhibitors have been synthesized and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8 [28].
• The activities of both isomers of 5 as inhibitors of mammalian dihydroorotase were marginally greater than that of the parent phosphinic acid 4, indicating a weak binding enhancement due to the phosphinothioic acid moiety [29].
• A number of BITs were synthesized with phosphonate and phosphinate acid-based leaving groups and were found to be potent inhibitors of HLE [30].

Analytical, diagnostic and therapeutic context of Phosphinic acid

• Crystals that were grown in its presence contained an L+-tartrate molecule from the crystallization buffer and not the phosphinate in the active site [31].

References