Indanylacetic acids as PPAR-delta activator insulin sensitizers

A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.     

Synthesis and pharmacological evaluation of 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines endowed with in vitro antiplatelet activity

A series of new 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines 3a-i have been synthesized and tested in vivo for the anti-inflammatory/analgesic/antipyretic effects and in vitro to evaluate the antiplatelet activity on guinea-pig platelet-rich plasma aggregated by collagen, adenosine-5'-diphosphate (ADP) and arachidonic acid (AA). Title compounds were ineffective in vivo; however, the pyrrolidino derivatives 3a and 3c exhibited an antiplatelet activity against all the aggregants differing from that of acetylsalicylic acid (ASA) while the 5-morpholino derivatives 3g-i showed the most potent ASA-like antiplatelet activity.     

Benzobistriazinones and related heterocyclic ring systems as potent, orally bioavailable positive allosteric AMPA receptor modulators

AMPA receptors (AMPARs) are an important therapeutic target in the CNS. A series of substituted benzobistriazinone, benzobispyrimidinone and related derivatives have been prepared with high potency and selectivity for the allosteric binding site of AMPARs. Further improvements have been made to previously reported series of positive AMPAR modulators and these compounds exhibit excellent in vivo activity and improved in vivo metabolic stability with up to 100% oral bioavailability in rat.     

Estrogen receptor binding affinity and uterotrophic activity of triphenylhaloethylenes

Radiohalogenated estrogens have considerable potential for estrogen receptor-directed imaging and therapy for cancers which contain such receptors. In an effort to evaluate the potential of the triphenyl ethylene structure for such purposes we have synthesized 3 series of 2-halosubstituted triphenylethylenes containing oxygen functions in the 4 position of both aromatic rings attached to carbon 1 of the ethylene and tested their uterotrophic activity and competition for rat uterine low salt extractable, "cytosol" estrogen receptor. Most active, both as competitors for estradiol binding to estrogen receptors and by their ability to stimulate uterine growth are the 1,1-bis-4-hydroxyphenyl derivatives although the 1,1-bis-4-acetoxyphenyl derivatives also show good receptor affinity and demonstrate uterotrophic activities. However, since uterine cytosol contains enzymes which hydrolyze the acetates to the free phenols even during the incubation in the cold used for the competitive binding studies, a significant portion of the competition shown by the diacetates is probably due to their hydrolysis products, the free phenols. The 1,1-bis-4-methoxyphenyl derivatives are weak competitive binders and demonstrate uterotrophic activity only when administered at the higher, 20 micrograms, doses. Comparing the relative activities of various halogens at the 2 position, in each series the bromo and chloro derivatives generally were of similar activity and significantly more active than the corresponding iodo derivative. The non-halogen substituted derivatives were very good competitors for estrogen receptor binding but less active with regard to uterine growth stimulation, providing evidence that in vivo the vinyl halides would appear to be relatively stable to simple dehalogenation. Since they show reasonably good apparent affinities for the estrogen receptor and apparent in vivo stability, reflected by estrogenic activity, these halogen substituted triphenylethylene derivatives appear to be promising substrates for investigations of estrogen receptor directed imaging and therapy.     

Synthesis and cytotoxic activity of novel quinazolino-beta-carboline-5-one derivatives

A novel series of quinazolino-beta-carbolinone derivatives was synthesized and evaluated for their in vitro and in vivo anticancer activity. Many compounds have shown good in vitro activity in the range 1-8 microM concentration. Three of the compounds were further tested in nude mice bearing HT-29 colon cancer xenografts.     

Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase,anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease

A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood–brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ secretion levels. Moreover, one-third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically.     

In vivo activities of peptide and pseudo-peptide analogs of the C-terminal octapeptide of cholecystokinin on pancreatic secretion in the rat

Most studies measuring the agonist and antagonist activities of CCK analogs and derivatives on the exocrine pancreas have been done with in vitro models. However, extrapolation to the in vivo situation may be sometimes hazardous, due to the catabolism of the peptides by circulating and tissue peptidases, and to their eventual interaction with various endogenous factors. The present experiments were organized to measure the efficacy and potency on pancreatic secretion of the rat in vivo of a series of CCK 8 analogs whose binding and activity had been previously measured on guinea-pig and rat isolated acini. The molecules tested were derivatives of Boc-(Nle 28-Nle 31)-CCK 26–33 (1), and comprised 2-phenylethylester derivatives, des-Phe derivatives, and a series of pseudo-peptides with a “reduced” bond CH2-NH replacing the peptide bond in position 28–29 to 32–33. They were perfused in anaesthetized rats, and the outputs of sodium, bicarbonate and total protein were measured. All of the derivatives studied had in vivo the same efficacy as (1) on the output of protein, and were 10 to 500 times less potent. For most compounds, the relative order of potencies measured in vivo was similar to that measured in vitro on amylase secretion by rat acini. However, the derivatives with reduced bonds in positions 28–29 and 29–30 were respectively 3 and 2 times less potent in vivo, relative to (1), while derivatives with reduced bonds in positions 30–31, 31–32 and 32–33 were 1.5 to 2.5 times more potent in vivo. The 2-phenylethylester derivatives were 7 and 9 times as potent in vitro as in vivo. The des-Phe derivative, which had in vitro antagonist properties on guinea-pig acini, and acted like a partial agonist on rat acini, was in vivo a complete agonist and was relatively 300 times as potent in vivo as in vitro. These results indicate that the metabolism of the peptides and/or their interaction with endogenous factors may change appreciably the effect of CCK derivatives on pancreatic secretion of the rat in vivo.     

Synthesis and biological activity of new anti-inflammatory compounds containing the 1,4-benzodioxine and/or pyrrole system

A series of substituted derivatives containing the 1,4-benzodioxine or pyrrole nucleus are described. All the newly synthesized compounds were examined for their in vitro and in vivo anti-inflammatory activity. Several derivatives, including (S)-2, 14 and 17, showed more anti-inflammatory activity in vivo in these assays (rat paw oedema induced by carrageenan) than the known classical anti-inflammatory agent ibuprofen, whereas other compounds like 1 were equipotent to ibuprofen. Compound 17 was the most outstanding derivative because of its remarkable in vivo anti-inflammatory activity. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.     

Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.     

Synthesis, biological evaluation and structural determination of beta-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors

Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.     

The design of 8,8-dimethyl[1,6]naphthyridines as potential anticonvulsant agents

Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.     

Synthesis and biological evaluation of five-membered heterocycles fused to cyclopenta[c]thiophene as new antitumor agents

A series of 10 derivatives 2-6 issued from the fusion of various five-membered heterocycles to cyclopenta[c]thiophene were evaluated for potential anticancer activity in the NCI's in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, four were found to be cytotoxic allowing us to point out some structure-activity relationships. The oxazolidinone derivatives 2a-c displayed further in vivo antitumor activity in the hollow fiber assay and standard xenograft testing developed at the NCI.     

Synthesis and biological activity of novel macrocyclic antifungals. modification of the tyrosine moiety of the lipopeptidolactone FR901469.

A series of tyrosine-modified derivatives of the macrocyclic lipopeptidolactone FR901469 have been prepared and evaluated for in vitro and in vivo antifungal activity and for hemolytic activity towards red blood cells. Compound 14 displayed significantly reduced hemolytic potential at 1mg/mL and a comparable protective effect to FR901469 in a mouse candidiasis model.     

Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions

A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.     

Synthesis and antibacterial activity of O-substituted nocathiacin I derivatives

The synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.     

Synthesis and antitumor activity of duocarmycin derivatives: modification at the C-7 position of segment-A of A-ring pyrrole compounds

A series of the C7-substituted A-ring pyrrole derivatives of duocarmycin were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. All of the C7-substituted A-ring pyrrole compounds decreased potency in vitro and in vivo. However, some showed strong antitumor activity with T/C values less than 0.3. Among them, the 7-formyl compound 5d showed remarkable potent in vivo antitumor activity and low peripheral blood toxicity, which were equal to 2c.     

Novel coumarin derivatives as potential antidyslipidemic agents

A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.     

Synthesis and biological evaluations of novel indenoisoquinolines as topoisomerase I inhibitors

A series of novel indenoisoquinoline derivatives were synthesized. The anticancer activities of these molecules were tested in human cancer cell lines A549, HepG2, and HCT-116. These compounds were also tested for their activity of topoisomerase I (top1) inhibition. Among them, compound 25 was found to be 10-times more potent in cell-killing activity for both cell lines HepG2 and HCT-116 than reported compound 11, with IC(50) of 0.019 and 0.093μM, respectively. Compound 25 was also found to have stronger top1 inhibition activity than 11 in our inhibition assay. Further in vivo evaluations of compound 25 are in progress and will be reported in due course.     

New analogues of mifepristone with more dissociated antiprogesterone activities

Mifepristone (RU 486 or RU 38486) possesses strong antiprogesterone and antiglucocorticoid along with moderate antiandrogen properties, which would limit its use in some therapeutic applications. In a search for more dissociated derivatives, the hydroxy substituent and the propynyl group in position 17 of the RU 486 series was replaced by a spiroether group, which is known to induce specific affinity for the progestin receptor in steroid series. The substituents in the para position of the 11 beta-phenyl group, leading to the most potent derivatives in the RU 486 series, were retained. The new derivatives have been studied in vitro for their relative binding affinities (RBAs) for the steroid receptor and in vivo for their hormonal and antihormonal activities. The selected compounds, RU 46556 and RU 49295 display the following properties: in vitro, like RU 486, they show a strong RBA for the rabbit progestin receptor, but a much lower one for the rat thymus glucocorticoid receptor; in vivo they are about three times more active than RU 486 for inducing abortion in rats, but unlike the latter they are devoid of any antiglucocorticoid activity on the thymus weight in rats. These antiprogesterone effects have been confirmed on the deciduoma formation in rats and on the endometrial proliferation in rabbits. However, in contrast to RU 486 in the latter test, some progestomimetic activity has been observed. RU 46556 and RU 49295 are now under extensive pharmacological study.     

Pleuromutilin derivatives having a purine ring. Part 1: new compounds with promising antibacterial activity against resistant Gram-positive pathogens

In the course of our research aimed at the discovery of metabolic stable pleuromutilin derivatives with more potent antibacterial activity against Gram-positive pathogens than previous analogues, a series of compounds bearing a purine ring were prepared and evaluated. From SAR studies, we identified two promising compounds 85 and 87, which have excellent in vitro activity against a number of Gram-positive pathogens, including existing drug-resistant strains, and potent in vivo efficacy.