Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

The chemistry and biological activity of heterocycle-fused quinolinone derivatives: A review.

Among all heterocycles, the heterocycle-fused quinolinone scaffold is one of the privileged structures in drug discovery as heterocycle-fused quinolinone derivatives exhibit various biological activities allowing them to act as anti-inflammatory, anticancer, antidiabetic, and antipsychotic agents. This wide spectrum of biological activity has attracted a great deal of attention in the field of medicinal chemistry. In this review, we provide a comprehensive description of the biological and pharmacological properties of various heterocycle-fused quinolinone scaffolds and discuss the synthetic methods of some of their derivatives.

Design and synthesis of an aminopiperidine series of γ-secretase modulators.

The design, synthesis, and SAR of cyclic diamines as novel γ secretase modulators (GSMs) are presented in this Letter. Starting from information in the literature and in-house cyclic diamines library, we have found a 3(S)-aminopiperidine as a potent structure for lowering Aß42 production both in vitro and in vivo.

7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors.

To identify compounds with strong mPGES-1 inhibitory activity and clear in vitro ADME profile, we optimized the lead compound 1 by carrying our substitutions at the C(7)- and C(8)-positions. Replacement of the bromine atom of 1 with various substituents led to identification of the phenyl group as the best C(7)-substituent giving strong inhibitory activity with good in vitro ADME profile. Further SAR examination on both the C(2)- and the C(7)-phenyl groups provided compound 39 as the best candidate for further development. Compound 39 exhibited strong mPGES-1 inhibitory activity (IC50=4.1 nM), potent cell-based functional activity (IC50=33 nM) with good mPGES-1 selectivity (over 700-fold), excellent in vitro ADME profile, and good oral absorption in rat PK study.

Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors.

We have previously reported 7-bromo-2-(2-chrolophenyl)-imidazoquinolin-4(5H)-one (1) as a novel potent mPGES-1 inhibitor. To clarify the essential functional groups of 1 for inhibition of mPGES-1, we investigated this compound structure-activity relationship following substitution at the C(4)-position and N-alkylation at the N(1)-, the N(3)-, and the N(5)-positions of 1. To prepare the target compounds, we established a good methodology for selective N-alkylation of the imidazoquinolin-4-one, that is, selective alkylation of 1 at the N(3)- and N(5)-positions was achieved by use of an appropriate base and introduction of a protecting group at the nitrogen atom in the imidazole part, respectively. Replacement of the C(4)-oxo group with nitrogen- or sulfur- linked substituents gave decreased inhibitory activity for mPGES-1, and introduction of alkyl groups on the nitrogen atom at the N(1)-, the N(3)-, and the N(5)-positions resulted in even larger loss of inhibitory activity. These results revealed that the C(4)-oxo group, and the hydrogen atoms at the N(5)-position and the imidazole part were the best substituents.

Asymmetric synthesis of the carbon-14-labeled selective glucocorticoid receptor modulator using cinchona alkaloid catalyzed addition of 6-bromoindole to ethyl trifluoropyruvate.

We describe in this study the asymmetric synthesis of radioisotope (RI)-labeled selective glucocorticoid receptor modulator. This synthesis is based on optimization of the cinchona alkaloid catalyzed addition of 6-bromoindole to ethyl trifluoropyruvate and Negishi coupling of zinc cyanide to the 6-bromoindole moiety. [¹4C] Labeled (-)-{4-[(1-{2-[6-cyano-1-(cyclohexylmethyl)-1H-indol-3-yl]-3,3,3-trifluoro-2-hydroxypropyl}piperidin-4-yl)oxy]-3-methoxyphenyl}acetic acid (-)-1 was synthesized successfully with high enantioselectivity (>99% ee) and sufficient radiochemical purity.

Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors.

The imidazoquinoline derivative 1 was found as a novel mPGES-1 inhibitor. Optimization of 1 led to the identification of the 2-chlorophenyl group at the C(2)-position and the quinolone structure at the C(4)-position. Compound 33, the most potent synthesized compound, showed excellent mPGES-1 inhibition (IC(50)=9.1nM) with high selectivity (>1000-fold) over both COX-1 and COX-2.

Synthesis and structure-activity relationship of tricyclic carboxylic acids as novel anti-histamines.

A series of tricyclic carboxylic acids having 6-amino-pyrimidine-2,4(1H,3H)-dione with piperazino or homopiperazino moiety linked by propylene, were synthesized and evaluated for their affinity toward human histamine H(1) receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice, bioavailability in rats, and their anti-inflammatory activity in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, dibenzoxazepine carboxylic acid 13b showed both histamine H(1) receptor antagonistic activity and anti-inflammatory activity in vivo. In addition, 13b exhibited low affinity toward α(1) receptor and low occupancy of H(1) receptor in the brain. It is therefore, believed that 13b is a potential candidate for development as 3rd generation anti-histamine.

Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H(1) antagonists.

A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, were synthesized and evaluated for their affinity toward human histamine H(1) receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H(1)-receptor antagonistic activity and anti-inflammatory activity in vivo model.

Synthesis and biological evaluation of novel 9-substituted-8-hydroxyadenine derivatives as potent interferon inducers.

Recently we reported the adenine derivatives 3a-d as novel interferon (IFN) inducers. In the present study, we conducted a detailed structure-activity relationship study of analogues of 3a-d with respect to their IFN-inducing activity, mainly focusing on the N(9)-position of the adenine. From this study, we found that introduction of the 3-pyridylmethyl moiety was effective to increase in vitro activity, and compound 9ae was identified as being the most potent IFN inducer. This compound gave a minimum effective concentration (MEC) of 3 nM, which is comparable with that of R-848, a second generation IFN inducer. Compound 9ae also demonstrated potent IFN-inducing activity at a dose of 0.1 mg/kg by oral administration in mice. Furthermore, compound 9ae induced IFN in monkeys in a dose dependent manner, with a potency superior to that of R-848. In addition, 9ae did not cause emesis in ferrets even at a dose of 30 mg/kg. In this study the maximum plasma concentration of 9ae was 1019 ng/mL (ca. 3.1 microM), which was approximately 1000-fold higher than the MEC value. Therefore, with respect to both the efficacy and the safety margin, compound 9ae (SM-276001) is considered to be a promising compound as an orally active IFN inducer.

Prodrugs of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine: potent interferon inducing agents in monkeys.

In order to improve the oral bioavailability of 9-benzyl-8-hydroxy-2-(2-hydroxyethylthio)adenine (SM-295072), a potent interferon (IFN) inducing agent, we synthesized prodrugs of it by utilizing the hydroxy groups at the C(2)-side chain and/or the C(8)-position. The carbonate prodrug at the C(8)-position was more effective than that at the C(2)-side chain for oral absorption in rats. Among the compounds prepared, compound 6 demonstrated the most preferable prodrug properties, and the maximum plasma concentration of 6 was approximately 4-fold higher than that of SM-295072. Furthermore, compound 6 was dose-dependently absorbed in monkeys by oral administration, and exhibited a potent IFN-inducting activity that correlated well with its plasma drug concentration.

Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities.

In order to create novel compounds which possess potent interferon (IFN) inducing activities with excellent oral bioavailabilities, a series of 8-hydroxyadenines, which have various alkoxy or alkylthio moieties at the adenine C(2)-position, were synthesized and evaluated. The introduction of hydrophobic groups was not considered to be effective for potentiating the IFN-inducing activity, but several compounds having hydrophilic groups were effective. Among the compounds tested, compound 13f induced IFN from the dosage of 0.03 mg/kg, which was approximately 100-fold more potent than that of Imiquimod, and showed an excellent oral bioavailability (F=40%) which was 10-fold improved over 5, a lead compound (F=4%).

Synthesis and structure-activity relationships of 2-amino-8-hydroxyadenines as orally active interferon inducing agents.

Recently, we have reported the 8-hydroxyadenine derivatives (2-4) as a novel class of interferon (IFN) inducing agents. In the present study, a series of 8-hydroxyadenines, which possess various amino moieties at the adenine C(2)-position, were synthesized and evaluated for their ability to induce endogenous IFN in comparison to the known active agent, Imiquimod. Among the compounds prepared, compound 9o possessing a 2-methoxyethylamino group at C(2)-position of adenine was found to exhibit potent IFN inducing activity in vivo. Compound 9o induced IFN from the dosage of 0.1 mg/kg, which was 30-fold potent than that of Imiquimod, and showed a good oral bioavailability (F=81%).

Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents.

In order to create novel, topical anti-inflammatory compounds exhibiting more potent activities than lead compound CX-659S (1), we designed and synthesized various derivatives of 1 focusing on the uracil N(1)- and N(3)-substituents, and evaluated their anti-inflammatory activities via inhibition of the picryl chloride-induced contact hypersensitivity reaction (CHR) in mice. In the course of our structure and activity relationship study, we found that compounds 6k, 6q, and 6r inhibited by approximately 50% the CHR, at 0.1 mg/ear. These activities were essentially equipotent with that of Tacrolimus, a strong immunosuppressant.

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.

A novel structural class of potent inhibitors of NF-kappa B activation: structure-activity relationships and biological effects of 6-aminoquinazoline derivatives.

In this study, we have investigated the roles of substituents on the terminal phenyl ring at the C(4)-position of the quinazoline core to complete the structure-activity relationships (SARs) of our NF-kappa B activation inhibitors. Among them, compound 12j afforded highly potent inhibitory activity toward NF-kappa B transcriptional activation with IC(50) value of 2 nM, along with an excellent in vivo efficacy by reducing the edema formation seen in carrageenin-induced inflammation of the rat hind paw.

Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects.

Recently we reported the adenine derivatives (2-4) as new interferon (IFN) inducers. In the present study, we conducted a detailed structure and activity relationship study of 4 and its related derivatives on IFN inducing activity. From this study, we found that compound 4 exhibited the most potent IFN inducing activity in vitro with a minimum effective concentration of 0.01 microM, and 4 also showed strong IFN-inducing activity at doses of more than 0.3mg/kg by oral administration in mice. This potency was 10-fold stronger than that of Imiquimod. Moreover, 4 did not cause emesis in ferrets even at doses as high as 10mg/kg, whereas, 80% of animals were emetic when orally administered with the same dose of Imiquimod. These results indicate that compound 4 is superior to Imiquimod with respect to efficacy and safety.

Inhibitory activities of novel pyrimidine derivatives on the contact hypersensitivity reaction.

In order to obtain novel topically applied anti-inflammatory compounds containing an inexpensive anti-oxidative moiety without chirality, we synthesized compound 2c derivatives having a di-tert-butylphenol moiety, and evaluated by topical administration their anti-inflammatory potentials on picryl chloride-(PC) induced contact hypersensitivity reaction (CHR) in mice. In the course of our structure-activity relationship (SAR) studies on the pyrimidine or the anti-oxidative moiety and the linker between them, the most potent compounds (10, 11) were obtained by the insertion of a C2 unit in compound 2c. The potencies of these compounds were 2-fold greater than that of 1. Compounds 10 and 11 were considered to be useful lead compounds having inexpensive anti-oxidative moieties without chirality.

Structure-activity relationships of 6-fluoroquinazolines: dual-acting compounds with inhibitory activities toward both TNF-alpha 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-alpha 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-alpha production.

Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation.

We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.