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Laser ultrasonic testing (LUT) can realize contactless and instantaneous non-destructive testing, but its signal-to-noise ratio must be improved in order to measure carbon fiber reinforced plastics (CFRPs). We have developed a mid-infrared (mid-IR) laser source optimal for generating ultrasonic waves in CFRPs by using a wavelength conversion device based on an optical parametric oscillator. This paper reports a comparison of the ultrasonic generation behavior between the mid-IR laser and the Nd:YAG laser. The mid-IR laser generated a significantly larger ultrasonic amplitude in CFRP laminates than a conventional Nd:YAG laser. In addition, our study revealed that the surface epoxy matrix of CFRPs plays an important role in laser ultrasonic generation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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-Hyp 24 ,Iva 25 ,Pya(4) 26 ,Cha 27,36 ,γMeLeu 28 ,Lys 30 ,Aib 31 ]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 Lys 30 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[d-Pro 24 ,Pya(4) 26 ,Cha 27,36 ,Aib 28,31 ,Lys 30 ]PYY(23-36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-d-proline (d-Hyp) 24 , isovaline (Iva) 25 , and γ-methylleucine (γMeLeu) 28 , not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[d-Hyp 24 ,Iva 25 ,Pya(4) 26 ,Cha 27,36 ,γMeLeu 28 ,Lys 30 ,Aib 31 ]PYY(23-36) (31, PYY-1119) at a dose of 0.03mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Melanin-concentrating hormone (MCH), a cyclic neuropeptide expressed predominantly in the lateral hypothalamus, plays an important role in the control of feeding behavior and energy homeostasis. Mice lacking MCH or MCH 1 receptor are resistant to diet-induced obesity (DIO) and MCH 1 receptor antagonists show potent anti-obesity effects in preclinical studies, indicating that MCH 1 receptor is a promising target for anti-obesity drugs. Moreover, recent studies have suggested the potential of MCH 1 receptor antagonists for treatment of non-alcoholic fatty liver disease (NAFLD). In the present study, we show the anti-obesity and anti-hepatosteatosis effect of our novel MCH 1 receptor antagonist, Compound A. Repeated oral administration of Compound A resulted in dose-dependent body weight reduction and had an anorectic effect in DIO mice. The body weight lowering effect of Compound A was more potent than that of pair-feeding. Compound A also reduced lipid content and the expression level of lipogenesis-, inflammation-, and fibrosis-related genes in the liver of DIO mice. Conversely, intracerebroventricular infusion of MCH caused induction of hepatic steatosis as well as increase in body weight in high-fat diet-fed wild type mice, but not MCH 1 receptor knockout mice. The pair-feeding study revealed the MCH-MCH 1 receptor system affects hepatic steatosis through a mechanism that is independent of body weight change. Metabolome analysis demonstrated that Compound A upregulated lipid metabolism-related molecules, such as acylcarnitines and cardiolipins, in the liver. These findings suggest that our novel MCH 1 receptor antagonist, Compound A, exerts its beneficial therapeutic effect on NAFLD and obesity through a central MCH-MCH 1 receptor pathway., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to explore intrauterine device (IUD) awareness and knowledge in a diverse, multiethnic population., Methods: We conducted a self-administered, anonymous survey addressing awareness of the IUD as a contraceptive method and knowledge about aspects of IUD use in a group of women aged 14 to 19 years. Demographic and medical information was obtained to compare awareness and knowledge between demographic groups. Chi-square, Fisher exact test, and t tests were used for analysis. Multiple logistic regression was utilized to confirm relationships., Results: Of the 106 respondents, 76.4% (81/106) were sexually active and 56.6% (60/106) reported a history of ever being pregnant. There were 21.1% (33/106) of respondents who had heard of the IUD as a contraceptive method. Of the subjects who had heard of the IUD, 39.4 % (13/33) were able to identify key features of the IUD. Although a history of pregnancy was predictive of having heard of the IUD, age, insurance status, education, and all other demographic factors were not associated with IUD awareness., Conclusion: Over 70% of the adolescents had not heard of the IUD and less than half of adolescents who had heard of the IUD were able to identify key features about this contraceptive method. The lack of knowledge of this effective and safe contraceptive option is concerning given that most participants were at high risk for unintended pregnancy., (Copyright © 2012 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure-activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn 294 and Asp 123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4'-fluoro-N-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1'-biphenyl]-4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Through the screening of our in-house chemical compound library, we found a novel melanin-concentrating hormone (MCH) receptor antagonist, T-226296, a (-) enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4-carboxamide. T-226296 exhibited high affinity for cloned human and rat MCH receptors (SLC-1) in receptor binding assays (IC50=5.5+/-0.12 nM for human SLC-1; 8.6+/-0.32 nM for rat SLC-1). T-226296 had high selectivity over other receptors, including the second subtype of the MCH receptor, SLT (MCH2), transporters and ion channels. In Chinese hamster ovary (CHO) cells expressing human SLC-1, T-226296 reversed the MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, inhibited MCH-induced intracellular Ca2+ increase, and also inhibited MCH-stimulated arachidonic acid release. In rats, oral administration of T-226296 (30 mg/kg) almost completely suppressed the food intake induced by intracerebroventricular injection of MCH. These results clearly indicate that T-226296 is a novel, orally active and selective MCH receptor antagonist that will be promising for further exploring the physiology and pathophysiology of MCH-SLC-1 signaling.