Design and synthesis of novel diphenyl oxalamide and diphenyl acetamide derivatives as anticonvulsants.

A series of novel N(1) -substituted-N(2) ,N(2) -diphenyl oxalamides 3a-l were synthesized in good yield by stirring diphenylcarbamoyl formyl chloride (2) and various substituted aliphatic, alicyclic, aromatic, heterocyclic amines in DMF and K(2) CO(3) . Also 2-substituted amino-N,N-diphenylacetamides 5a-m were designed by pharmacophore generation and synthesized by stirring 2-chloro-N,N-diphenylacetamide (4) and various substituted amines in acetone using triethyl amine as a catalyst. All the synthesized compounds were screened for anticonvulsant activity in Swiss albino mice by MES and ScPTZ induced seizure tests. Neurotoxicity screening and behavioral testing was also carried out. Some of the synthesized test compounds were found to be more potent than the standard drug.

Inhalation by design: novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors.

We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC(50) of 0.05muM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.

1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties.

A series of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid were synthesized in order to obtain new compounds with potential anti-inflammatory activity, analgesic activity and lower ulcerogenic potential. All compounds were evaluated for their anti-inflammatory activity by the carrageenan induced rat paw edema test method. The compounds possessing potent anti-inflammatory activity were further tested for their analgesic, ulcerogenic and antioxidant activities. Out of all tested compounds, the compounds 3, 7, 17 and 20, showed significant reduction in rat paw edema induced by carrageenan treatment. These compounds showed significant analgesic effect and at an equimolar oral doses relative to flurbiprofen were also found to be non-gastrotoxic in rats. Compound 17 was evaluated as the lead compound having more anti-inflammatory activity (81.81%) than the reference drug (79.54%), low ulcerogenic potential and protective effect on lipid peroxidation.

Kinetics of activation and in vivo muscarinic receptor binding of N-(2-bromoethyl)-4-piperidinyl diphenylacetate: an analog of 4-DAMP mustard.

4-DAMP mustard (N-2-chloroethyl)-4-piperidinyl diphenylacetate) has been shown to selectively and irreversibly inhibit muscarinic receptors. In an attempt to increase the rate of formation and peak concentration of the reactive intermediate, an analog [N-(2-bromoethyl)-4-piperidinyl diphenylacetate (4-DAMP bromo mustard)] was synthesized and the molecular formula confirmed by mass analysis. The 4-DAMP bromo mustard was shown to cyclize in phosphate buffer (pH 7.4) to the corresponding aziridinium ion with a first-order rate constant (k1) of 0.071 min-1 at 0 degrees C. At 25 degrees C and 37 degrees C, the formation of the aziridinium ion was nearly instantaneous (100% cyclized within 15 sec) at neutral pH. The rate constants (k2) for the hydrolysis of the aziridinium ion at 25 degrees C and 37 degrees C (pH 7.4) were 0.0027 and 0.010 min-1, respectively, in excellent agreement with the published rate constants for the hydrolysis of the aziridinium ion formed from 4-DAMP mustard. In vivo treatment with 4-DAMP bromo mustard in rats resulted in irreversible inhibition of muscarinic receptor binding in peripheral, but not central nervous system, tissues, suggesting that the quickly formed aziridinium ion does not penetrate the blood-brain barrier.

Metabolism of arylacetic acids. 3. The metabolic fate of diphenylacetic acid and its variation with species and dose.

1. [carboxy-14C]Diphenylacetic acid has been administered to seven primate species including man, and four other mammals and the qualitative and quantitative aspects of its elimination determined. 2. In most species, 50-100 percent of the administered 14C was excreted in the urine in 48 h; 2-30 percent of the dose was recovered unchanged in the 24 h urine. 3. In all species the only urinary metabolite detected by radiochromatogram scanning was diphenylacetylglucuronide (10-70 percent of dose). Reverse isotope dilution additionally revealed the formation of trace amounts (less than 1 percent of dose) of the glycine conjugate by four species and of the taurine conjugate by the cat. No evidence was found for the formation of a glutamine conjugate. 4. The influence of dose on the pattern of metabolism and excretion of diphenylacetic acid has been studied in the rat. In this species diphenylacetic acid undergoes extensive elimination and enterohepatic circulation.

Synthesis and pharmacological properties of some new 1,1-diarylacetic acid derivatives.

A series of 13 new 1,1-diphenylacetic acid derivatives was synthesized via common transformations of 2-phenyl-2-(p-nitrophenyl) propio- and butyronitriles. The compounds were submitted to pharmacological screening. 2-Phenyl-2-(p-aminophenyl)propionamide (VIII) showed high anticonvulsant activity.

Actions of some esters of 3,3-dimethylbutan-1-ol (the carbon analogue of choline) on the guinea-pig ileum.

1 Estimates were made of the affinity constants for postganglionic acetylcholine receptors of the guinea-pig ileum of the esters of 3,3-dimethylbutan-1-ol with benzilic, (+/-)-cyclohexylphenylglycollic, (+/-)-mandelic, and diphenylacetic acids.2 Attempts were made to check the competitive nature of the antagonism by using as wide a range of concentrations of antagonist as possible, consistent with their limited solubility, and by testing some of the compunds in the presence of a known competitive antagonist.3 By comparing the affinities with those of the corresponding quaternary nitrogen compounds, the contribution made by the positive charge in the onium group to the binding by receptors may be assessed and has been found to be variable. The carbon analogue of benziloylcholine has about one-tenth of its affinity, that of (+/-)-cyclohexylphenylglycolloylcholine has only about one-sixtieth of its affinity, but that of (+/-)-mandelylcholine has slightly higher affinity than that of (+/-)-mandelylcholine itself.4 3,3-Dimethylbutylacetate appeared to be a partial agonist with an affinity constant of about 2.6 x 10(3). The contribution made by the positive charge to the binding of acetylcholine at these receptors therefore seems likely to lie within the range observed with antagonists and there is no reason to believe that there is necessarily greater intimacy of association by agonists than by antagonists.5 Although the C-C and /#/N-C bonds in -CMe(3) and -/#/NMe(3) are similar in length, the groups do not occupy the same volume in solution in water.