Series Of Phenoxyacetic Acids Research Articles

Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold

Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.

Chromatographic Behaviour Predicts the Ability of Potential Nootropics to Permeate the Blood-Brain Barrier

The log BB parameter is the logarithm of the ratio of a compound’s equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k′. The second aim was to estimate the brain’s absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k′ were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism.

Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain

Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.

Phenoxyacetic acids as PPARδ partial agonists: Synthesis, optimization, and in vivo efficacy

A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.

In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat: Structure-activity relationships

We have examined, relative to clofibric acid (CPIB), the effects of a chemical series of phenoxyacetic acids and of two asymmetric CPIB analogues, the R(+)- and S(−)-enantiomers of 2-(4-chlorophenoxy) propionic acid (4-CPPA) and 2-(4-chlorophenoxy)butyric acid (4-CPBA), on hepatic peroxisome proliferation both in vivo and in vitro utilizing cholesterol-fed rats and primary cultured rat hepatocytes respectively. Peroxisome proliferation was assessed by measuring changes in peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities as well as by electron microscopic examination of 3,3'-diaminobenzidine-stained liver slices. CPIB and enantiomers of 4-CPPA and 4-CPBA (0.6 mmol/kg/day for 7 days) produced hepatomegaly, lowered serum cholesterol levels, and caused 4.7- to 12.9-fold and 2.9- to 6.1-fold increases in hepatic FACO and LH activities, respectively, in cholesterol-fed rats. Electron micrographs of liver cells showed an increased number of peroxisomes from cholesterol-fed rats given S(−)-4-CPBA and CPIB. Likewise, these compounds (0.03 to 1.0 mM) induced FACO and LH in primary rat hepatocyte cultures after 72 hr. R(+)- and S(−)-Enantiomers of 4-CPPA produced similar concentration-dependent and maximal increases in both FACO and LH activities, whereas enantiomeric selectivity [ s(−) > R(+)] for the induction of these two enzymes was observed with the isomers of 4-CPBA. The increases in the activities of FACO and LH caused by S(−)-4-CPBA were similar to those elicited by 1.0 mM CPIB (58.6- and 9.8-fold respectively). These results show that the enantiomers of 4-CPPA and 4-CPBA induce the peroxisome proliferation-associated enzymes FACO and LH in vivo and in vitro, and that the S(−)-isomer of 4-CPBA causes a greater induction of FACO and LH in vitro than its corresponding R(+)-isomer, indicating that these two enzymes are induced in an enantioselective manner. Optimal induction of the peroxisome proliferation-associated enzymes FACO and LH in rat hepatocyte cultures was produced by phenoxyacetic acids possessing (1) a chlorine atom at the 4-position of the phenyl ring, (2) a dimethyl or mono-ethyl substitution at the α-carbon atom of the carboxylic acid side chain; and (3) an S(−)-orientation for chiral analogues possessing a mono-ethyl group at the α-carbon atom of the carboxylic acid side chain. These results indicate that changes in the chemical and stereoisomeric structures of phenoxyacetic acids alter peroxisome proliferation and are consistent with a hypothesized receptor-mediated mechanism, and by employing the proper enantiomeric form, a greater dissociation of beneficial lipid lowering actions from adverse carcinogenic effects of peroxisome proliferators may be obtained.

Physico‐chemical factors affecting uptake by roots and translocation to shoots of weak acids in barley

AbstractThe uptake from solution of maleic hydrazide, flamprop and a series of phenoxyacetic acids by roots, and their subsequent translocation to shoots, was measured in barley. Both uptake and translocation increased as the pH of the solution decreased, the magnitude of the change varying amongst the chemicals tested. Uptake by roots could be accounted for by the ion‐trap mechanism, which assumes that entry of the chemicals occurs largely by passive diffusion of the undissociated form of the acids, with passage of the anions across the cell membranes being very slow. The ratio of the permeability of the cell membranes to the undissociated and dissociated forms of the acids was estimated from the accumulation in roots, and in the phenoxyacetic acid series this ratio was maximal (4×105) for compounds of intermediate lipophilicity. Maleic hydrazide and flamprop had much lower ratios, 1.8×102 and 103 respectively; the value for flamprop was much less than for phenoxyacetic acids of similar lipophilicity, such as 2, 4‐ dichlorophenoxyacetic acid, indicating that lipophilicity may not be the sole factor determining the behaviour of weak acids in plants. Translocation to shoots was approximately proportional to the chemical concentrations in the roots.

Chemical structure-biological activity relationships in the phenoxyacetic acid series.

Many phenoxyacetic acids show interesting hypocholesterolaemic and anti-lipolytic activity. So reported Thorp [1] 74% of the 116 investigated phenoxyacetic acids to be active. Hundreds of analogues have since been synthesised and some have successfully entered medical practice.

Studies on the Relation of Chemical Structure to Plant Growth-Regulator Activity in the Pineapple Plant. V. Post-Harvest Delay of Senescence of Pineapple Fruit

The results of testing 369 compounds for post-harvest delay of senescence of pineapple fruit have been presented. Included were 94 phenoxyacetic acids, 43 other phenoxy acids, 23 phenylacetic acids, 15 hydrocinnamic acids, 20 compounds related to phenoxy acids, nine benzoic and seven salicylic acids, 48 naphthalene derivatives, 22 indole acids, five hydrazine derivatives, and eight cinnamic acids. Some 76 of the chemicals tested showed activity, and 29 were highly active in delaying senescence. The relationship of some of the chemical structures to senescence inhibition as a manifestation of plant-growth regulator activity is discussed. In the phenoxyacetic acid series, high activity was obtained from several of the halogen-substituted acids and not among the methyl-substituted acids. A few of the methyl-substituted acids did have moderate activity, however. In the phenoxy-a-propionic acid series, high activity was observed not only for a number of halogen-substituted acids but also for those with methyl ...

Species differences in the albumin binding of 2,4,6-trinitrobenzaldehyde, chlorophenoxyacetic acids, 2-(4′-hydroxybenzeneazo)benzoic acid and some other acidic drugs—the unique behavior of rat plasma albumin

Binding of chlorophenoxyacetic acids and other drugs to albumins from different species was studied by equilibrium dialysis and by two optical probes, 2,4,6-trinitrobenzaldehyde (TNBal) and 2-(4′-hydroxybenzeneazo)benzoic acid (HBABA). Rat plasma albumin behaves abnormally, compared with plasma albumin fraction V preparations from ten other species, in its interaction with HBABA in the presence of certain drugs (thyroxine, indolacetates and chlorophenoxy acids). HBABA may be a useful tool for determining the binding of anionic drugs to various albumins (other than pig and horse albumins). No relationship was discovered between albumin binding and hypocholesterolemic activity in vivo in a series of phenoxyacetic acids related to clofibrate (Atromid-S).

An Atypical Growth of Cabbage-Seedling Roots. I. Morphology, Histology, and Induction Conditions

1. The induction and appearance of atypical growths on the roots of cabbage seedlings under the influence of parachlorophenoxyacetic acid (POA) are described. 2. Synthetic growth substances inducing such growth are limited to the phenoxyacetic acid series and naphthoxyacetic acid. 3. A number of sources of reduced nitrogen augment the action of the growth substance in production of these tumors. Nonspecificity of the nitrogen sources is indicated by the effectiveness of a number of amino acids and amides and of ammonium chloride. 4. Formation of the atypical growths is inhibited by buffering the medium at pH 6.0 or above; whereas buffers at pH 5.5 or below have no inhibitory effect. 5. Histological preparations of typical roots and of the atypical growths show that the tumors consist essentially of fasciated plates of lateral root tissue, with growth occurring in a massive fashion. 6. Origin of the tumors is from the pericycle, or the pericycle and endodermis combined, of the primary root. Xylem, cortex, and cpidermis are inactive in producing the growths and do not seem to be affected by POA.

Mode of action of growth regulators in plants.

Hansch and Muir1 have shown that a free ortho position is required for growth regulatory activity in the phenoxyacetic acid series (Avena straight-growth test), and have suggested that the active compound reacts “with a substrate at two points, first by means of the carboxyl group, and second at a position ortho to the attachment of the carboxyl group”. This explanation does not account for Wain's finding2 that one hydrogen on the α-carbon atom was essential for activity (Went pea test).