3302-11-2Relevant academic research and scientific papers
Pharmacodynamic and pharmacokinetic analysis of CNS-active constitutional isomers of valnoctamide and sec-butylpropylacetamide - Amide derivatives of valproic acid
Mawasi, Hafiz,Shekh-Ahmad, Tawfeeq,Finnell, Richard H.,Wlodarczyk, Bogdan J.,Bialer, Meir
, p. 72 - 78 (2015)
Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are CNS-active closely related amide derivatives of valproic acid with unique anticonvulsant activity. This study evaluated how small chemical changes affect the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three constitutional isomers of SPD [sec-butylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)] and of VCD [tert-butylethylacetamide (TED)]. The anticonvulsant activity of SID, TID, and TED was comparatively evaluated in several rodent anticonvulsant models. The PK-PD relationship of SID, TID, and TED was evaluated in rats, and their teratogenicity was evaluated in a mouse strain highly susceptible to teratogen-induced neural tube defects (NTDs). sec-Butylisopropylacetamide and TID have a similar PK profile to SPD which may contribute to their similar anticonvulsant activity. tert-Butylethylacetamide had a better PK profile than VCD (and SPD); however, this did not lead to a superior anticonvulsant activity. sec-Butylisopropylacetamide and TED did not cause NTDs at doses 4-7 times higher than their anticonvulsant ED50 values. In rats, SID, TID (ip), and TED exhibited a broad spectrum of anticonvulsant activity. However, combined anticonvulsant analysis in mice and rats shows SID as the most potent compound with similar activity to that of SPD, demonstrating that substitution of the isobutyl moiety in the SPD or VCD molecule by tert-butyl as well as a propyl-to-isopropyl replacement in the SPD molecule did not majorly affect the anticonvulsant activity.
Syntheses and evaluation of anticonvulsant profile and teratogenicity of novel amide derivatives of branched aliphatic carboxylic acids with 4-aminobenzensulfonamide
Hen, Naama,Bialer, Meir,Wlodarczyk, Bogdan,Finnell, Richard H.,Yagen, Boris
experimental part, p. 4177 - 4186 (2010/09/04)
Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide were synthesized and evaluated in the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol seizure (scMet) tests. Fourteen of the synthesized amides had an anticonvulsant ED50 of 50 values of 7.6, 9.9, and 9.4 mg/kg and remarkable protective index (PI = TD 50/ED50) values of 65.7, 50.5, and 53.2, respectively. These potent sulfanylamides caused neural tube defects only at doses markedly exceeding their effective dose. The anticonvulsant properties of these compounds make them potential candidates for further development as new, potent, and safe AEDs.
Synthesis and evaluation of antiallodynic and anticonvulsant activity of novel amide and urea derivatives of valproic acid analogues
Kaufmann, Dan,Bialer, Meir,Shimshoni, Jakob Avi,Devor, Marshall,Yagen, Boris
experimental part, p. 7236 - 7248 (2010/07/04)
Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and lifethreatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED50 values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain. 2009 American Chemical Society.
Thioketene Syntheses, VI. Stable Thioketenes via Thionation of Sterically Hindered Acyl Chlorides
Schaumann, Ernst
, p. 2755 - 2765 (2007/10/02)
Sterically hindered acyl chlorides 11 are accessible via alkylation of the ester 1 or via chain elongation of the ketones 4 by one carbon atom in practicable, though multi-step reaction sequences.Action of phosphorus pentasulfide/pyridine on 11 leads to t
STERIC EFFECTS IN SYSNTHESIS - STERIC LIMITS TO THE ALKYLATION OF NITRILES AND CARBOXYLIC ACIDS
MacPhee, John-Anthony,Dubois, Jacques-Emile
, p. 775 - 778 (2007/10/02)
The steric limits to the alkylation of aliphatic nitriles and carboxylic acids have been investigated in some detail.For the experimental conditions considered (ionization by i-Pr2NLi in THF followed by alkylation with RI/THF/HMPA) the most hindered nitriles R-CN and carboxylic acids R-CO2H have the same secondary alkyl group R=t-BuiPrCH-, but different tertiary, i.e.R=t-BuiPrEtC- or i-Pr3C- for RCN and R=Et2MeC for RCO2H.A comparison of the relative merits of alkylation of esters, carboxylic acids, and nitriles is considered.
