Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids.

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer.

Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma.

A radioiodinated ligand, [125I]SB-236636 [(S)-(-)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]3-[125I]i odo phenyl]2-ethoxy propanoic acid], which is specific for the gamma isoform of the peroxisomal proliferator activated receptor (PPARgamma), was developed. [125I]SB-236636 binds with high affinity to full-length human recombinant PPARgamma1 and to a GST (glutathione S-transferase) fusion protein containing the ligand binding domain of human PPARgamma1 (KD = 70 nM). Using this ligand, we characterized binding sites in adipose-derived cells from rat, mouse and humans.

[[omega-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents.

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]-benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies.

Characterization of a new, highly specific, beta 3-adrenergic receptor radioligand, [3H]SB 206606.

The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a high specific activity compound, [3H]SB 206606. This new, potentially specific, beta 3-adrenergic receptor ligand was characterized by binding studies using membranes from both Chinese hamster ovary K1 cells transfected with the rat beta 3-adrenergic receptor and rat interscapular brown adipose tissue, where beta 1-, beta 2-, and beta 3-adrenergic receptor subtypes are known to coexist. [3H]SB 206606 was found to bind to a single population of binding sites in both preparations.

Synthesis and antiallergic activity of 2-hydroxy-3-nitro-1,4-naphthoquinones.

A selection of novel 2-hydroxy-3-nitro-1,4-naphthoquinones are shown to be potent inhibitors of rat passive cutaneous anaphylaxis (PCA) and to have highest potency with alkyl substitution at both C-6 and C-7. The most potent compounds were 7c and 7e which produced a 50% inhibition in the rat PCA test at doses of about 10 micrometerM/kg following subcutaneous administration and showed activity after oral administration. Related 4-hydroxy-3-nitro-2(1H)-naphthalenones had no effect on rat PCA in doses up to 500 micrometerM/kg.

2-cyano-1,3-dicarbonyl compounds with antiallergic activity.

A number of 2-cyanoindan-1,3-diones and 3-cyano-4-hydroxycoumarins have been prepared and assessed for potential antiallergy activity as measured by their ability to inhibit passive cutaneous anaphylaxis in the rat, mediated by rat serum containing antigen specific IgE. The structural requirements for activity were similar not only for both series of compounds but also for the analogous 2-nitroindan-1,3-diones and 4-hydroxy-3-nitrocoumarins previously reported. The most active compounds were 2-cyano-5,6-diethylindan-1,3-dione (4e) and 3-cyano-6,7-diethyl-4-hydroxycoumarin (11h).

Antiallergic activity of omega-nitroacetophenones.

Selected omega-nitroacetophenones, formed by the alcoholic cleavage of 2-nitroindandiones, have been shown to inhibit the homocytotropic antibody-antigen induced passive cutaneous analhylaxis reaction in the rat. The enzymatic cyclization of these derivatives to the parent nitroindandione has been demonstrated both in vivo and in vitro and this process is suggested as a possible prerequisite to biological activity.

4-hydroxy-3-nitro-2-quinolones and related compounds as inhibitors of allergic reactions.

The synthesis and biological activity of a number of 4-hydroxy-3-nitro-2-quinolones are discussed and compared with their related hydroaromatic analogs. Antiallergic activity has been assessed by their ability to inhibit the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.

Antiallergic activity of 4-hydroxy-3-nitrocoumarins.

Twenty-four substituted 4-hydroxy-3-nitrocoumarins have been prepared for nitration of the corresponding 4-hydroxycoumarins. All were found to possess antiallergic activity as measured by the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.