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At least 19 recordsLinked to original sources
PubMed1999

Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorophenyl)pentanoic acid.

(RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acidB (GABAB) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R, 5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12. HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABAA or GABAB receptor sites and was inactive as an agonist or an antagonist at GABAB receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABAA receptor sites, and in agreement with the findings for (S)-baclofen, 12 did not interact significantly with GABAB receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 microM), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 microM) as an inhibitor of GABAB binding. Accordingly, 11 (EC50 = 150 +/- 23 microM) was shown to be weaker than 2 (EC50 = 11 +/- 1 microM) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABAB antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 microM) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.

Animals↗
PubMed1997

The lipoic acid analogue 1,2-diselenolane-3-pentanoic acid protects human low density lipoprotein against oxidative modification mediated by copper ion.

1,2-Diselenolane-3-pentanoic acid, in which the sulfur atoms of alpha-lipoic acid are replaced with selenium, displayed markedly different antioxidant properties when compared to alpha-lipoic acid. 1,2-Diselenolane-3-pentanoic acid was unable to inhibit protein oxidative modification of human low density lipoprotein (LDL) and bovine serum albumin induced by copper ion or hydroxyl radical, whereas alpha-lipoic acid showed significant protection. However, 1,2-diselenolane-3-pentanoic acid was able to inhibit the formation of lipid peroxidation products in LDL after oxidation by copper, while alpha-lipoic acid did not. Hence the diselenium compound exerts its effects in a lipophilic environment whilst lipoic acid exerts its effects in a hydrophilic environment. These differences in antioxidant activities of the two compounds may be explained, at least in part, by their differing partition coefficients.

Antioxidants↗
PubMed2001

Pentanoic acid, a novel protein synthesis stimulant for Chinese Hamster Ovary (CHO) cells.

Nine carboxylic acids were tested to evaluate their effects on recombinant fusion protein production and cell growth of Chinese Hamster Ovary (CHO) cells. Pentanoic acid was demonstrated to have the highest enhancement effect on the protein biosynthesis of CHO cells among the acids tested. Pentanoic acid also had less growth suppression effects compared with butyrate. The optimal induction time and concentration of pentanoic acid for a 120-h batch culture were 72 h and 1 mM, respectively. Apoptosis (programmed cell death) was observed in the serum-free batch culture of CHO cells using a cell death detection ELISA kit. The addition of butyrate accelerated the rate of apoptosis of CHO cells whereas the addition of pentanoate did not. These results confirmed that pentanoic acid was a better stimulant for protein biosynthesis in animal cell culture than butyrate.

Journal Article↗
PubMed1997

S-2-amino-5-(2-nitroimidazol-1-yl)pentanoic acid: a model for potential bioreductively activated prodrugs for inhibitors of nitric oxide synthase (NOS) activity.

Treatment of 1,1-dimethylethyl S-(2-1,1-dimethylethoxycarbonylamino)-5-bromopentanoate with 1-potassio-2-nitroimidazole, followed by deprotection, afforded S-2-amino-5-(2-nitroimidazol-1-yl)pentanoic acid, which was reduced to S-2-amino-5-(2-aminoimidazol-1-yl)pentanoic acid. This aminoimadazole inhibited rat brain nitric oxide synthase (NOS) activity 3.2 times more potently than did the nitro analogue. Thus S-2-amino-5-(2-nitroimidazol-1-yl)pentanoic acid is a potent prodrug which may be bioreductively activated to a NOS inhibitor in hypoxic solid tumours.

Animals↗
PubMed1989

The effects of 4-pentenoic and pentanoic acid on the hypoxic rat atria.

When exposed to hypoxia, the isolated rat atria released lactate into the bathing medium and underwent a rise in resting tension and a decline of the contractions frequency. In some of them, it also occurred a complete cessation of the pacemaker activity. Atria from 24-h fasted rats, when compared to those from fed ones, exhibited a lower lactate output, a higher rise in resting tension, a faster decay of the contraction frequency and an increased occurrence of atrial arrest. In both the fed and fasted rats atria, some triacylglycerol lipolysis remained throughout the hypoxic incubation. Addition of 2 mM 4-pentenoic acid abolished the lipolytic activity and reduced lactate output in both groups of atria. In the fed rats atria it also accelerated the decrease of the pacemaker frequency. Pentanoic acid reduced lactate output in both groups of atria and in those from fed rats it did not alter lipolysis but increased the rise in resting tension, the decline of the pacemaker frequency and the occurrence of atrial arrest. Present data indicate that although 4-pentenoic acid inhibits fatty acid oxidation and endogenous lipolysis, it was not able to reduce the noxious effects of hypoxia. Since the effects of 4-pentenoic acid were rather similar to those of fasting and pentanoic acid, they might be ascribed to the accumulation of its own oxidative metabolites which could be detrimental for the hypoxic atria.

Animals↗
PubMed1978

Inhibitors of polyamine biosynthesis VI: 2,5-Diamino-2-(cyanomethyl) pentanoic acid, a potential irreversible inhibitor of ornithine decarboxylase.

(+/-)-2,5-Diamino-2-)cyanomethyl)pentanoic acid was obtained by the reaction of chloracetonitrile with the anion obtained by treatment of 3-(benzylideneamino)-2-piperidinone with sodium hydride, followed by hydrolysis in the presence of trifluoroacetic anhydride. The target compound was isolated as the monohydrochloride salt of the lactam. The compound was synthesized as a potential irreversible inhibitor of the enzyme L-ornithine decarboxylase by the mechanism generally known as suicide or Kcat inhibition. The synthesized compound produced no inhibition of the enzyme ornithine decarboxylase obtained from rat prostate gland. The inactivity of the target compound is attributed to the hydrophilicity of the cyanomethyl group.

Amino Acids, Diamino↗
PubMed2004

Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor.

The potency, efficacy, and pharmacokinetic properties of IDN-6556 (3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid), a first-in-class caspase inhibitor in clinical trials for the treatment of liver diseases, were characterized in vivo in rodent models. In the mouse alpha-Fas model of liver injury, i.p. administration of IDN-6556 resulted in marked reduction of alanine aminotransferase (ALT), apoptosis, and caspase activities at a dose of 3 mg/kg. At this dose, IDN-6556 was also effective when given up to 2 h before alpha-Fas and as late as 4 h after alpha-Fas administration. In both the alpha-Fas and d-galactosamine/lipopolysaccharide (D-Gln/LPS) model, ED(50) values in the sub-milligram per kilogram range were established after a number of routes of administration (i.p., i.v., i.m., or p.o.), ranging from 0.04 to 0.38 mg/kg. Efficacy was also demonstrated in the rat D-Gln/LPS model with 67 and 72% reductions in ALT activities after i.p. and p.o. treatment with IDN-6556 (10 mg/kg), respectively. Pharmacokinetic analysis in the rat demonstrated rapid clearance after i.v., i.p., and s.c. administration with terminal t(1/2) ranging from 46 to 51 min. Low absolute bioavailability after p.o. administration was seen (2.7-4%), but portal drug concentrations after oral administration were 3-fold higher than systemic concentrations with a 3.7-fold increase in the terminal t(1/2), indicating a significant first-pass effect. Liver concentrations remained constant after oral administration for at least a 4-h period, reaching a C(max) of 2558 ng/g liver at 120 min. Last, 51 +/- 20 and 4.9 +/- 3.4% of IDN-6556 was excreted intact in bile after i.v. and p.o. administration, respectively. This evaluation indicates that IDN-6556 has marked efficacy in models of liver disease after oral administration and thus, is an excellent candidate for the treatment of liver diseases characterized by excessive apoptosis.

Animals↗
PubMed1988

The effects of 4-pentenoic and pentanoic acids on the isolated rat atria.

The peak developed tension and the pacemaker frequency of the isolated atria from fed and fasted rats, declined progressively during the incubation in a glucose-free medium containing 2-deoxyglucose. The atria from fed rats exhibited a faster decline than those from fasted rats, which was associated to a slower triacylglycerol lipolysis. 4-Pentenoic acid inhibited the lipolysis of both groups of atria but did not alter the atrial contractile performance. However, it enhanced the decline of the pacemaker frequency in the atria from fasted rats whereas, in contrast, it alleviated the decline in the fed atria. n-Pentanoic acid ameliorated the impairment of the contractile and pacemaker activities in both groups of atria, without affecting the lipolysis. It was concluded that, since the inhibition of the intramyocardial lipolysis did not correlate with changes of the atrial functions, 4-pentenoic acid was not appropriate to assess about the contribution of endogenous triacylglycerol to the maintenance of the atrial contractile and pacemaker activities.

Animals↗
PubMed1992

Characterization of antigastrin activity in vivo of CR 2194, a new R-4-benzamido-5-oxo-pentanoic acid derivative.

The antigastrinic activity, in vivo, of CR 2194 (R-4-(3-chlorobenzamido)-5-(8-azaspiro[4.5]decan-8-yl) -5-oxo pentanoic acid) was assessed in various animal species. CR 2194 antagonized pentagastrin-stimulated gastric acid secretion in the rat (ID50 = 11 mg/kg i.v.), dog (ID50 = 5.9 mk/kg i.v. or 28.8 mg/kg os) and cat (ID50 = 15.5 mg/kg i.v.). CR 2194, in the cat, inhibited both competitively and non-competitively the gastric acid secretion stimulated with increased doses of pentagastrin, with a pA2 of 4.89. In the rat and in the dog the antagonism seemed to be non-competitive and the respective pD'2 calculated were 4.54 and 4.42. The interaction of CR 2194 with the gastrin receptors appeared reversible, as demonstrated by the return to normal values of the acid output after the conclusion of the i.v. infusion, during pentagastrin continuous stimulation in the dog. The antigastrin activity was specific: CR 2194 was unable to antagonize the gastric acid secretion stimulated by carbachol or histamine in the rat up to the dose of 100 mg/kg. CR 2194 was effective to antagonize the gastric acid secretion stimulated by gastrin release after meal ingestion in the Heidenhain pouch dog model. The ID50 calculated was 2.89 mg/kg after oral administration. All these characteristics make CR 2194 an important compound in the investigation of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.

Animals↗
PubMed1975

Effects of pentanoic acid and 4-pentenoic acid on the intracellular fluxes of acetyl coenzyme A in Tetrahymena.

Cultures of Tetrahymena pyriformis were incubated for 1 hour with a mixture of acetate, pyruvate, and pentanoate with only one substrate labeled at a time and with the position of the label chosen so that [1-14-C]acetyl coenzyme A was an early product of the metabolism of each substrate. The appearance of label in CO2, lipids, glycogen, glutamate, and alanine were measured and results interpreted in terms of a previously developed three-compartment model of metabolism, which was found to quantitatively describe the data even when two of the flux rates (the flux of acetyl-CoA from the peroxisomal to the outer mitochondrial compartment and from the outer mitrochondrial to the inner mitochondrial compartment) were set equal to zero. This reduction in the number of independent parameters leads to the model being overdetermined and to a probably unique fit of the three-compartment model tof the present data and to previous data when octanoate was the fatty acid substrate. Pentanoate was metabolized to a greater extent than octanoate and did not inhibit growth. Pentanoate inhibited acetate utilization in both the inner mitochondrial and peroxisomal compartments as indicated by a reduction in the incorporation of label from [1-14-C]acetate into lipids and into CO2, but there was no difference in oxidation of [2-14-C]pyruvate when pentanoate was the fatty acid substrate as compared to octanoate. Glyconeogenesis was inhibited when pentanoate was substituted for octanoate. Similar experiments were performed on cells treated with 4-pentenoic acid. The effects of 4-pentenoic acid were essentially the same whether octanoate or pentanoate was the fatty acid substrate, i.e. inhibition of glyconeogenesis from all labeled substrates and inhibition of [2-14-C]pyruvate oxidation. The results indicate that the effects of pentanoate are largely confined to the peroxisomal and the inner mitochondrial compartments whereas the effects of 4-pentenoic acid are confined to the peroxisomal and outer mitochondrial compartments.

Acetates↗