Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives

Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp²⁴,Iva²⁵,Pya(4)²⁶,Cha^27,36,γMeLeu²⁸,Lys³⁰,Aib³¹]PYY(23–36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (C_max) and longer time at maximum concentration (T_max). Compounds 5 and 10, modified with 20?kDa PEG at the N-terminus and eicosanedioic acid at the Lys³⁰ side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low C_max and long T_max, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.     

Discovery of orally efficacious RORγt inverse agonists. Part 2: Design,synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.     

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.     

Effects of Dietary Supplementation with Fish Scales-Derived Collagen Peptides on Skin Parameters and Condition: A Randomized,Placebo-Controlled,Double-Blind Study

Fish scales-derived collagen peptides (CPs) are characterized by their specific amino acid composition with a high concentration of glycine, proline and hydroxyproline. These amino acids have been known to exert beneficial effects on human skin. The aim of the present study was to examine the effects of collagen peptides obtained from fish scales on changes in periorbital wrinkles, facial skin hydration, and skin elasticity in healthy women aged 30–60 years. In the present randomized, placebo-controlled, double-blind trial, 71 subjects consumed a 20 mL beverage containing 3000 mg of CPs or placebo once per day over 12 weeks. Significant decreases in periorbital wrinkles (p?<?0.05) were observed in the treatment group after 12 weeks of CPs ingestion compared to the control group. This study also demonstrated a consistent trend of enhanced facial skin moisture (p?<?0.001) and skin elasticity (p?<?0.001) by dietary intake of CPs without any side effects or adverse events. These findings indicate that fish-derived CPs hold great promise as a natural supplement with cutaneous anti-aging properties.     

Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models

Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson’s, and Huntington’s diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson’s and Huntington’s diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.     

A double-blind,placebo-controlled,randomised clinical study of the effect of pork collagen peptide supplementation on atherosclerosis in healthy older individuals

We examined whether baPWV could be affected by pork collagen peptide (CP) ingestion. Seventy subjects were randomized into two groups (2.5 g/day CP and 2.5 g/day placebo). A significant reduction in baPWV was observed in the CP group compared to the placebo group. This study demonstrated that pork CP may contribute to the prevention of atherosclerosis in elderly.     

Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent,selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp² carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp³ carbon atoms to increase the molecular complexity, measured by fraction sp³ (Fsp³). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC₅₀ value of 11?nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNa_V1.5 channels, and was identified as an orally bioavailable compound.     

Discovery of DS42450411 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4-aminopyrimidine derivatives

Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure–activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.     

Cricket mate selection as a spatial discounting phenomenon without learning

Many animals prefer small local benefits to large but temporally or spatially distant benefits, and this preference is termed “temporal discounting” or “spatial discounting.” Although temporal discounting has been studied in many taxa, only a limited number of papers have primarily focused on spatial discounting. Here, a mate-choice experiment was conducted using female house crickets (Acheta domesticus) tasked with selecting between a non-attractive local male and an attractive distant male; training procedures were not performed. The results showed that females that had never heard the calling songs of males exhibited spatial discounting behavior. This finding may be key to determining the fundamental differences between temporal and spatial discounting.     

Endogenous Fusarium Endophthalmitis During Treatment for Acute Myeloid Leukemia,Successfully Treated with 25-Gauge Vitrectomy and Antifungal Medications

Endogenous fungal endophthalmitis (EFE) caused by disseminated fusariosis is a rare condition that generally has a poor outcome, even with intensive therapy. Here, we describe a case in which this type of EFE was diagnosed with vitreous sampling and was successfully treated with 25-gauge vitrectomy and antifungals, including liposomal amphotericin B and voriconazole. A 16-year-old male patient undergoing treatment for acute myeloid leukemia complained of eye pain and blurred vision in his right eye. Treatment was initiated for a vitreous opacity, possibly associated with herpetic retinitis, but the patient worsened and he was referred to us. Right-eye visual acuity was limited to light perception. We suspected endogenous endophthalmitis and performed 25-gauge vitrectomy with antibiotic perfusion of ceftazidime, vancomycin, and voriconazole. Vitreous culturing revealed the presence of Fusarium solani species complex, and enhanced computed tomography revealed disseminated fusariosis lesions in the lung, spleen, and the soft tissue of the left upper arm. The patient received antifungal treatment with liposomal amphotericin B and voriconazole, and these conditions were eliminated. Visual acuity recovered to 20/400 after additional vitrectomy for tractional retinal detachment and was maintained at this level during the 6-month follow-up period. The success of our treatment allowed the capture of optical coherence tomography images of the retina during fusarium-associated endogenous endophthalmitis and the follow-up period. Furthermore, this case showed that immediate vitrectomy for suspected EFE and intensive treatment can lead to a good clinical outcome.