Dual-acting Compounds Research Articles

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists.

Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

Renewing embryonic stem cells

Embryonic stem cells have great potential in medicine, but the current methods used to grow them prevent their therapeutic use. A dual-action compound has been discovered that may help solve this problem.

Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation.

We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha production with an ED50 value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-alpha production in vivo as well as oral bioavailability.

Structure–Activity relationships of 6-fluoroquinazolines: dual-Acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation

We synthesized various 6-fluoro-7-(1-piperazino)quinazolines based on the structure of 1 and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Among these compounds, 7a, having the 3,4-(methylenedioxy)phenyl moiety at the C(4)-position of the quinazoline ring, showed both inhibitory activities. Furthermore, the oral treatment with 7a exhibited an anti-inflammatory effect in rats with adjuvant arthritis as well as an inhibitory activity toward LPS-induced TNF-α production.

Structure-activity relationships of 6-nitroquinazolines: dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation.

We synthesized various 6-nitroquinazolines by modifying the structure of compound 1 and evaluated their inhibitory activities toward both TNF-alpha production and T cell proliferation responses. The presence of the unsubstituted piperazine ring at the C(7)-position was required for both inhibitory activities. In this series of compounds, 5d and 5f, containing the 4-fluorophenyl and 3,4-difluorophenyl moiety, respectively, at the C(4)-position, showed the suppressing effects toward both responses with low cell growth inhibition. Furthermore, the oral administration of these compounds mentioned above at doses of 30 and 100 mg/kg also resulted in significant inhibition of TNF-alpha production induced by LPS in vivo.

Structure–activity relationships of quinazoline derivatives: dual-acting compounds with inhibitory activities toward both TNF-α production and T Cell proliferation

We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.

Overview of a rational approach to design type I 17 β-hydroxysteroid dehydrogenase inhibitors without estrogenic activity: chemical synthesis and biological evaluation

Hormone-sensitive diseases such as breast cancer are health problems of major importance in North America and Europe. Endocrine therapies using antiestrogens for the treatment and the prevention of breast cancer are presently under clinical trials. Antiestrogens are drugs that compete with estrogens for the estrogen receptor without activating the transcription of estrogen-sensitive genes. However, an optimal blockade of estrogen action could ideally be achieved by a dual-action compound that would antagonize the estrogen receptor and inhibit the biosynthesis of estradiol. Type I 17 β-hydroxysteroid dehydrogenase (17 β-HSD) was chosen as a key steroidogenic target enzyme to inhibit the formation of estradiol, which is the most potent estrogen. This article describes a rational approach that could lead to the development of compounds that exhibit both actions. The chemical syntheses of estradiol derivatives bearing a bromoalkyl and a bromoalkylamide side chain at the 16 α-position are summarized. Two parameters were studied for biological evaluation of our synthetic inhibitors: (1) the inhibition of estrone reduction into estradiol by type I 17 β-HSD, and (2) the proliferative/antiproliferative cell assays performed on the estrogen-sensitive ZR-75-1 breast tumor cell line. First, the substitution of the 16 α-position of estradiol by bromoalkyl side chain led to potent inhibitors of type I 17 β-HSD, but the estrogenic activity remained. Secondly, an alkylamide functionality at the 16 α- or 7 α-position of estradiol cannot abolish the estrogenic activity without affecting considerably the inhibitory potency on type I 17 β-HSD. In conclusion, the best dual-action inhibitor synthesized showed an IC 50 of 13±1 μM for type I 17 β-HSD, while displaying antiestrogenic activity at 1.0 μM. Despite the fact that we did not obtain an ideal dual-action blocker, we have optimized several structural parameters providing important structure–activity relationship.

The design of dual-acting compounds with PAF receptor antagonistic and 5-lipoxygenase inhibitory activities

The design of dual-acting compounds with PAF receptor antagonistic and 5-lipoxygenase inhibitory activities

In vitro activity of Ro 24-6392, a novel ester-linked co-drug combining ciprofloxacin and desacetylcefotaxime

In preliminary in vitro susceptibility tests Ro 24-6392 (desacetylcefotaxime with a 3'-ciprofloxacin substitution) demonstrated activity against a wide spectrum of aerobic bacteria, 98.6% of strains being inhibited by less than or equal to 8 mg/l. Of the commonly isolated species tested, only enterococcal strains were resistant (MICs greater than or equal to 32 mg/l). The potency of Ro 24-6392 was generally between that observed for the two hydrolysis components, except in the case of Providencia stuartii and penicillin-resistant pneumococci isolates which were more susceptible to Ro 24-6392. This new dual-action compound appears to be slightly more active than the previously studied peer drug Ro 23-9424, principally because of the superior activity of the fluoroquinolone component, ciprofloxacin.