Hiroki Kakuta

Cyclooxygenase-1-Selective Inhibitors Are Attractive Candidates for Analgesics That Do Not Cause Gastric Damage. Design and in Vitro/in Vivo Evaluation of a Benzamide-Type Cyclooxygenase-1 Selective Inhibitor

Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4-(trifluoromethyl)benzamide ( 18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1 IC 50 = 0.80 +/- 0.05 microM, COX-2 IC 50 = 210 +/- 10 microM). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.

The First Potent Subtype‐Selective Retinoid X Receptor (RXR) Agonist Possessing a 3‐Isopropoxy‐4‐isopropylphenylamino Moiety, NEt‐3IP (RXRα/β‐dual agonist)

Retinoid X receptor (RXR) agonists (rexinoids) are attracting much attention for their use in treatment of cancers, including tamoxifen‐resistant breast cancer and taxol‐resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype‐selective RXR agonists have been found. We previously reported an RXRα‐preferential agonist 4‐[N‐methanesulfonyl‐N‐(5,5,8,8‐tetramethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)amino]benzoic acid (6 a). The RXR agonistic activity is much less than that of well‐known RXR agonists. To develop potent, less‐lipophilic, and subtype‐selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well‐known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6‐[N‐ethyl‐N‐(3‐isopropoxy‐4‐isopropylphenyl)amino]nicotinic acid (NEt‐3IP: 7 a) and 6‐[N‐ethyl‐N‐(3‐isobutoxy‐4‐isopropylphenyl)amino]nicotinic acid (NEt‐3IB: 7 c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover, NEt‐3IP (7 a) was found to be the first RXRα/β‐selective (or RXRα/β‐dual) agonist. Being potent, less lipophilic, and having RXR subtype‐selective activity, NEt‐3IP (7 a) is expected to become a new drug candidate and to be a useful biological tool for clarifying each RXR subtype function.

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.

Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl)phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)]. These compounds are more active than vancomycin [MIC=2.0microg/mL (MRSA), 125microg/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria.

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity.

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRalpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.

Antimalarial Cation-dimers Synthesized in Two Steps from an Inexpensive Starting Material, Isonicotinic Acid

Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low‐cost antimalarials, the MAP series 6–10, bis‐cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis‐cation‐type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1,1′‐(1,12‐dodecanediyl)bis[4‐[(buthylamino)carbonyl]pyridinium bromide], MAP‐412 (6 d), exhibited a potent antimalarial activity (ED50=8.2 mg kg−1). Being prepared at low cost, our bis‐cation‐type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.

Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers.

RXR permissive heterodimers are reported to be activated differently depending upon the chemical structure of RXR agonists, but the relationship of agonist structure to differential heterodimer activation has not been explored in detail. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid, NEt-3IP) and evaluated the RXR-, PPAR/RXR-, and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analogue (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analogue (5i) and n-propoxy analogue (5k) but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia or type 2 diabetes.

Retinoid X receptor ligands: a patent review (2007 – 2013)

Introduction: Retinoid X receptors (RXRs) are nuclear receptors that act as ligand-dependent transcription factors. RXRs function as homodimers or as heterodimers with other nuclear receptors, such as retinoic acid receptors, PPARs, liver X receptors, farnesoid X receptor, vitamin D receptor or thyroid hormone receptors. RXR ligands (agonists or antagonists) show various physiological effects, depending on their partner receptors. RXR agonist bexarotene (Targretin®) is used for the treatment of cutaneous T-cell lymphoma in clinical practice. RXR agonists were also reported to be useful for treatment of type 2 diabetes, autoimmune disease and Alzheimers disease. RXR antagonists were also reported to be effective in type 2 diabetes treatment. Areas covered: Here patent applications (2007 – 2013) concerning RXR ligands are summarized, and the usefulness of RXR ligands as pharmaceutical agents is discussed. Expert opinion: RXR agonists show a wide variety of biological effects. However, they cause serious side effects, such as blood triglyceride elevation, hypothyroidism and others. Thus, for clinical application of RXR agonists, abrogation of these side effects is required. RXR heterodimer-selective agonists and RXR partial agonists exhibiting desired effects without side effects are expected to find clinical application.

In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs

Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents.

RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists.

Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum

Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains.