Biomedical subjects

J J Wright

Publications and source records attributed to J J Wright.

At least 19 recordsLinked to original sources

PubMed1992

Hypocholesterolemic activity of synthetic and natural tocotrienols.

Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

Animals↗

PubMed1992

Nonprostanoid prostacyclin mimetics. 2. 4,5-Diphenyloxazole derivatives.

4,5-Diphenyl-2-oxazolenonanoic acid (18b) was synthesized and found to inhibit ADP-induced aggregation of human platelets with an IC50 of 2.5 microM. Acid 18b displaced [3H]iloprost from human platelet membranes in a concentration-dependent fashion, consistent with 18b inhibiting platelet function by acting as a prostacyclin mimetic. By inserting a phenoxy ring into the side-chain moiety of 18b and systematically varying the pattern of substitution and length of the tethers, more potent inhibitors of platelet aggregation were identified. A phenoxy ring inserted centrally in the side chain proved to be the optimal arrangement but significant activity was observed when the aromatic ring was bound directly to the 2 position of the heterocycle. The meta-substituted cis-(ethenylphenoxy)acetic acid 37 is the most potent platelet aggregation inhibitor synthesized as part of this study with an IC50 of 0.18 microM. Acid 37 displaces [3H]iloprost from human platelet membranes with an IC50 of 6 nM. The trans-olefinic isomer of 37 (25p) is 72-fold weaker as an inhibitor of ADP-induced platelet aggregation, but the saturated derivative 25w (BMY 42393) is intermediate in potency. Structure-activity studies using 25w as a template focused on modification of the tethers intervening between the side-chain phenyl ring and the oxazole and carboxylate termini and substitution of the phenyl ring. These studies revealed that biological activity was sensitive to both the identity of the concatenating atoms and the pattern of ring substitution. The structure-activity relationships provide insight into the topographical relationship between the diphenylated oxazole ring and the carboxylic acid terminus that comprise the nonprostanoid prostacyclin mimetic pharmacophore.

Adenosine Diphosphate↗

PubMed1992

Nonprostanoid prostacyclin mimetics. 3. Structural variations of the diphenyl heterocycle moiety.

4,5-Diphenyl-2-oxazolenonanoic acid (2) and 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (3) were previously identified as nonprostanoid prostacyclin (PGI2) mimetics that inhibit ADP-induced aggregation of human platelets in vitro. The effects on biological activity of substitution and structural modification of the 4- and 5-phenyl rings of 3 was examined. Potency showed a marked sensitivity to the introduction of substituents to these aromatic rings and only the bis-4-methyl derivative 9j, IC50 = 0.34 microM, demonstrated enhanced potency compared to the parent structure 3, IC50 = 1.2 microM. Substitution at the ortho or meta positions of the phenyl rings, replacement by thiopheneyl or cyclohexyl moieties, or constraining in a planar phenanthrene system resulted in compounds that were less effective inhibitors of ADP-induced platelet aggregation. In contrast, variation of the heterocycle moiety revealed a much less stringent SAR and many 5- and 6-membered heterocycles were found to effectively substitute for the oxazole ring of 2 and 3. The diphenylmethyl moiety functioned as an effective isostere for 4,5-diphenylated heterocycles since 13aad showed similar platelet inhibitory activity to 3. With the exception of the 3,4,5-triphenylpyrazole derivative 13g, compounds presenting the (m-ethylphenoxy)acetic acid side chain discovered with 3 demonstrated enhanced potency compared to the analogously substituted alkanoic acid derivative. The structure-activity findings led to a refinement of a model of the nonprostanoid PGI2 mimetic pharmacophore.

Adenosine Diphosphate↗

PubMed1992

Inhibitors of blood platelet cAMP phosphodiesterase. 2. Structure-activity relationships associated with 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones substituted with functionalized side chains.

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives, substituted at the 7-position with functionalized side chains, was synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) as well as ADP- and collagen-induced platelet aggregation, in vitro. Structural modifications focused on variation of the side-chain terminus, side-chain length, and side-chain connecting atom. Functionality incorporated at the side-chain terminus included carboxylic acid, ester and amide, alcohol, acetate, nitrile, tetrazole, and phenyl sulfone moieties. cAMP PDE inhibitory potency varied and was dependent upon the side-chain terminus and its relationship with the heterocyclic nucleus. Methylation at N-1 or N-3 of the heterocycle diminished cAMP PDE inhibitory potency. Several representatives of this structural class demonstrated potent inhibition of ADP- and collagen-induced blood platelet aggregation and were half-maximally effective at low nanomolar concentrations. Amides 13d, 13f, 13h, 13k, 13m, and 13w are substantially more potent than relatively simply substituted compounds. However, platelet inhibitory properties did not always correlate with cAMP PDE inhibition across the series, probably due to variations in membrane permeability. Several compounds inhibited platelet aggregation measured ex vivo following oral administration to rats. Ester 11b, acid 12b, amide 13d, and sulfone 29c protected against thrombus formation in two different animal models following oral dosing and were found to be superior to anagrelide (2) and BMY 20844 (5). However, ester 11b and acid 12b demonstrated a unique pharmacological profile since they did not significantly affect hemodynamic parameters in dogs at doses 100-fold higher than that required for complete prevention of experimentally induced vessel occlusion in a dog model of thrombosis.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1992

Inhibitors of blood platelet cAMP phosphodiesterase. 3. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives with enhanced aqueous solubility.

Two series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives incorporating an additional site for acid salt formation were synthesized and evaluated as inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and ADP-induced platelet aggregation. The objective of this study was to identify compounds that blended potent biological activity with a satisfactory level of aqueous solubility. From a series of 7-aminoimidazo[4,5-b]quinolin-2-ones, biological and physical properties were optimally combined in the 1-piperidinyl derivative 11c. However, this compound offered no significant advantage over earlier studied compounds as an antithrombotic agent in an animal model of small vessel thrombosis. A series of 7-alkoxy alkanoic piperazinamide derivatives, in which the additional basic nitrogen atom was remote from the heterocyclic nucleus and accommodated in a secondary binding region of the cAMP PDE enzyme, demonstrated greater intrinsic cAMP PDE inhibitory activity. Structural modifications of this series focused on variation of the piperazine substituent and side-chain length. The lipophilicity of the N-substituent influenced biological potency and aqueous solubility, with substituents of seven carbon atoms or less generally providing acceptable solubility properties. The N-(cyclohexylmethyl)piperazinamide 21h was identified from this series of compounds as a potent inhibitor of platelet cAMP PDE, IC50 = 0.4 nM, and ADP-induced platelet aggregation, IC50 = 0.51 microM after a 3-min exposure and 0.1 microM after a 15-min exposure of platelet-rich plasma to the drug. Evaluation of 21h and representative analogues in vivo using a rabbit model of small vessel thrombosis revealed significantly greater antithrombotic efficacy compared to that of previously studied compounds with similar intrinsic biological activity measured in vitro but inferior aqueous solubility.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1992

Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic.

A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings.

Adenylyl Cyclases↗

PubMed1992

Hypersymmetry in a transcriptional terminator of Escherichia coli confers increased efficiency as well as bidirectionality.

Rho-independent transcriptional terminators in Escherichia coli usually consist of a GC-rich region encoding a sequence which allows the nascent transcript to form a stem-loop structure, and thereby apparently causes the RNA polymerase to pause; followed by an A-rich region on the DNA template strand, whose weak pairing to the consequently U-rich 3'-tail of the transcript is believed to aid release of the RNA. Quite commonly there is additional symmetry encoding, in the RNA, an A-rich sequence complementary to the 'tail', just upstream of the GC-rich motif. It has been pointed out by others that this should allow the termination of transcription in both directions. We hypothesized that it might also increase the efficiency of termination, for example by competing with the template DNA strand so as to help 'unzip' the 3'-end of the RNA from its complementary DNA. We have tested this hypothesis by deletion analysis of the hypersymmetric alpha-operon terminator, tL17. The results show that efficiency as well as bidirectionality is indeed adversely affected by deletion of the upstream A-rich sequence.

Base Sequence↗

PubMed1991

Radial coherence, wave velocity and damping of electrocortical waves.

Mean squared coherence was calculated as a function of frequency (1-32 Hz) and electrode separation (1-8 mm) from 64-channel extradural arrays on occipito-parietal association cortex of cats. A 2-parameter theoretical function was then fitted to sets of pooled estimates. The theoretical function described coherences between recording sites of small separation for linear, non-dispersive, dissipative waves moving on an infinite homogeneous plane medium, and driven by spatio-temporally noisy inputs. Residuals of fit were then plotted as a function of frequency and distance, and were found to show no systematic trends with frequency, but an irregular and generally increasing relation to distance. This was the result predicted for linear non-dispersive waves on a surface actually folded, and with significant additional wave action generated between electrodes. Further recordings of coherence from more widely separated electrodes indicated that boundary conditions were absorbing or remote, rather than closed or reentrant. The phase velocity for electrocortical waves obtained from autoregression estimates of temporal damping and parameters of fit to coherence, was found in the range 0.1-0.29 m/sec, and appeared independent of the direction of electrode alignment. This compares with the velocity of 0.33 m/sec for alpha waves earlier found by Lopes da Silva and Storm van Leeuwen.

Animals↗

PubMed1991

1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones--inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation.

A series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives was synthesized and evaluated as inhibitors of cAMP hydrolysis by a crude human platelet phosphodiesterase preparation and as inhibitors of ADP- and collagen-induced aggregation of rabbit blood platelets. The parent structure 7a, demonstrated potent inhibitory activity that was enhanced by the introduction of alkyl, alkoxy, or halogen substituents at the 5-, 6-, 7-, and 8-positions. Methylation at N-1 or N-3 produced weaker inhibitors of cAMP PDE and platelet aggregation. 1,3,9,9a-Tetrahydro-2H-imidazo[4,5-b]quinolin-2-ones (6) were found to be equipotent with their fully oxidized congeners (7). On the basis of platelet inhibitory properties in vitro, efficacy at preventing thrombus formation in animal models of thrombosis, and a favorable hemodynamic profile, 1,3-dihydro-7,8-dimethyl-2H- imidazo[4,5-b]quinolin-2-one (7o, BMY 20844) was selected for advancement into toxicological evaluation and clinical trial. An efficient synthesis of 7o is described.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1991

Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee).

A double-blind, crossover, 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.

Adult↗

PubMed1979