Non-thiazolidinedione antihyperglycemic agents. Part 5: asymmetric aldol synthesis of (S)-(-)-2-oxy-3-arylpropanoic acids.

Haigh, David; Birrell, Helen C.; Cantello, Barrie C. C.; Eggleston, Drake S.; Haltiwanger, R. Curtis; Hindley, Richard M.; Ramaswamy, Anantha; Stevens, Nicola C. Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Essex, UK. Tetrahedron: Asymmetry (1999), 10(7), 1353-1367. Publisher: Elsevier Science Ltd., CODEN: TASYE3 ISSN: 0957-4166. Journal written in English. CAN 131:144537 AN 1999:369514 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract Boron-mediated asym. aldol reactions of 4-[2-(2-benzoxazolylmethylamino)ethoxy]benzaldehyde with 2-oxyethanoyloxazolidinones contg. electron withdrawing, chelating, and bulky alkoxy and aryloxy groups, gave variable yields of syn-aldol adducts in high diastereoisomeric excess. These adducts were dehydroxylated in a sequence which complements the traditional Evans asym. alkylation strategy. Cleavage of the auxiliary from these intermediates afforded antihyperglycemic (S)-(-)-2-oxy-3-arylpropanoic acids in excellent enantiomeric excess. The target compds. were ?-alkoxy-4-[2-[(benzoxazolyl)amino]ethoxy]benzenepropanoic acid derivs. The biol. activity of the compds. thus prepd. was not reported here.

Non-thiazolidinedione antihyperglycemic agents. Part 4: synthesis of ( )-, (R)-(+)- and (S)-(-)-enantiomers of 2-oxy-3-arylpropanoic acids

. Haigh, David; Birrell, Helen C.; Cantello, Barrie C. C.; Hindley, Richard M.; Ramaswamy, Anantha; Rami, Harshad K.; Stevens, Nicola C. Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Essex, UK. Tetrahedron: Asymmetry (1999), 10(7), 1335-1351. Publisher: Elsevier Science Ltd., CODEN: TASYE3 ISSN: 0957-4166. Journal written in English. CAN 131:144536 AN 1999:369513 CAPLUS (Copyright (C) 2009 ACS on SciFinder (R)) Abstract The synthesis of a new series of potent 2-oxy-3-arylpropanoic acid antihyperglycemic agents in both racemic and non-racemic form is described. (the biol. activity of these compds. was not reported here). Resoln. of racemic acids is accomplished via amide formation with either (S)-2-phenylglycinol or (S)-4-benzyl-2-oxazolidinone as complementary resolving agents. The target compds. were ?-alkoxy-4-[2-[(2-benzoxazolyl)amino]ethoxy]benzenepropanoic acid derivs.

Rhodium carbenoid O-H insertion reactions with phenols; a facile method for the synthesis of trialkyl 2-aryloxyphosphonoacetates and their use in the preparation of 2-aryloxy-3-phenylpropanoates

Substituted phenols undergo a facile Rh carbenoid-mediated O-H insertion reaction with (EtO)2P(O)C(:N2)CO2R (I; R = Et, Me) to give 44-86% 2-aryloxyphosphonoacetates II (R1 = e.g., H, 4-Me, 4-Cl, 2-OH, 4-PhCH2O). Phenols contg. strongly electron withdrawing groups, bulky ortho-substituents or certain ortho-heteroatom substituents show reduced or variable yields. Catechol affords a mono-adduct which cyclizes to lactate III. Aniline inserts preferentially and exclusively over phenol in a competition reaction with I (R = Et) to give (EtO)2P(O)CH(NHPh)CO2Et. II are versatile intermediates in a prepn. of 2-aryloxy-3-phenylpropenoates IV by Wadsworth-Emmons reaction with benzaldehydes R2C6H4CHO (R2 = PhCH2O, 2-Cl, H). Dissolving Mg metal redn. provides a mild method for the conversion of propenoates IV into the corresponding propanoates.

Competing O-H insertion and  -elimination in rhodium carbenoid reactions; synthesis of 2-alkoxy-3-arylpropanoates

Rhodium(II) carboxylate catalyzed decompn. of diazo esters 3 (shown as I) and PhCH2C(CO2Et)N2 4 in the presence of alcs. or water results in formation of 2-alkoxy- or 2-hydroxy-3-arylpropanoates, resp., by O-H insertion in competition with cinnamates by elimination; the ratio of insertion to elimination is dramatically affected by the carboxylate ligand on rhodium. Use of methanol-d as the alc. confirms that the alkene does not arise by elimination from the initial alkoxyester product.

Insulin-releasing and metabolic effects of small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline

Much recent attention has focused on the GLP-1 receptor as a potential target for antidiabetic drugs. Enzyme resistant GLP-1 mimetics such as exenatide are now employed for the treatment of type 2 diabetes, but must be administered by injection. The present study has examined and compared the in vitro and in vivo metabolic actions of a small molecule GLP-1 receptor agonist 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB), with native GLP-1, exenatide and liraglutide. DMB significantly stimulated in vitro insulin secretion from BRIN-BD11 cells but with decreased molar potency compared to native GLP-1 or related mimetics. Administration of DMB in combination with glucose to mice significantly (P

Abnormal changes in voltage-gated sodium channels NaV1.1, NaV1.2, NaV1.3, NaV1.6 and in Calmodulin/calmodulin-dependent protein kinase II, within the brains of spontaneously epileptic rats and tremor rats

Voltage-gated sodium channels (VGSCs) play a crucial role in epilepsy. The expressions of different VGSCs subtypes are varied in diverse animal models of epilepsy that may reflect their multiple phenotypes or the complexity of the mechanisms of epilepsy. In a previous study, we reported that NaV1.1 and NaV1.3 were up-regulated in the hippocampus of the spontaneously epileptic rat (SER). In this study, we further analyzed both the expression and distribution of the typical VGSC subtypes NaV1.1, NaV1.2, NaV1.3 and NaV1.6 in the hippocampus and in the cortex of the temporal lobe of two genetic epileptic animal models: the SER and the tremor rat (TRM). The expressions of calmodulin (CaM) and calmodulin-dependent protein kinase II (CaMKII) were also analyzed with the purpose of assessing the effect of the CaM/CaMKII pathway in these two models of epilepsy. Increased expression of the four VGSC subtypes and CaM, accompanied by a decrease in CaMKII was observed in the hippocampus of both the SERs and the TRM rats. However, the changes observed in the expression of VGSC subtypes and CaM were decreased with an elevated CaMKII in the cortex of their temporal lobes. Double-labeled immunofluorescence data suggested that in SERs and TRM rats, the four subtypes of the VGSC proteins were present throughout the CA1, CA3 and dentate gyrus regions of the hippocampus and temporal lobe cortex and these were co-localized in neurons with CaM. These data represent the first evidence of abnormal changes in expression of four VGSC subtypes (NaV1.1, NaV1.2, NaV1.3 and NaV1.6) and CaM/CaMKII in the hippocampus and temporal lobe cortex of SERs and TRM rats. These changes may be involved in the generation of epileptiform activity and underlie the observed seizure phenotype in these rat models of genetic epilepsy.

Pioglitazone protects HDL(2&3) against oxidation in overweight and obese men

The worldwide epidemic of obesity is a major public health concern and is persuasively linked to the rising prevalence of diabetes and cardiovascular disease. Obesity is often associated with an abnormal lipoprotein profile, which may be partly negated by pioglitazone intervention, as this can influence the composition and oxidation characteristics of low-density lipoprotein (LDL). However, as pioglitazone's impact on these parameters within high-density lipoprotein (HDL), specifically HDL(2&3), is absent from the literature, this study was performed to address this shortcoming.

Toluene Dioxygenase Catalysed synthesis and reactions of cis-diol metabolites derived from 2 and 3-methoxy phenols

Using toluene dioxygenase as biocatalyst, enantiopure cisdihydrodiol and cis-tetrahydrodiol metabolites, isolated as their ketone tautomers, were obtained from meta and ortho methoxyphenols. Although these isomeric phenol substrates are structurally similar, the major bioproducts from each of these biotransformations were found at different oxidation levels. The relatively stable cyclohexenone cis-diol metabolite from meta methoxyphenol was isolated, while the corresponding metabolite from ortho methoxyphenol was rapidly bioreduced to a cyclohexanone cis-diol. The chemistry of the 3-methoxycyclohexenone cis-diol product was investigated and elimination, aromatization, hydrogenation, regioselective O-exchange, Stork−Danheiser transposition and O-methylation reactions were observed. An offshoot of this technology provided a two-step chemoenzymatic synthesis, from meta methoxyphenol, of a recently reported chiral fungal metabolite; this synthesis also established the previously unassigned absolute configuration.