Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 31
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem ; 85: 117238, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37028120

ABSTRACT

Farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)γ are nuclear receptor 1 superfamily of transcription factors. FXR and PPARγ agonists have been individually investigated in clinical trial of anti-diabetic agents in the patients with nonalcoholic fatty liver disease (NAFLD). Regarding recent agonist development, the partial agonists for FXR and PPARγ are drawing attention from the standpoint of avoiding overactive responses caused by full agonists. In this article, we report that 18 with a benzimidazole scaffold possesses FXR/PPARγ dual partial agonistic activity. In addition, 18 shares the ability to reduce cyclin-dependent kinase 5-mediated phosphorylation of PPARγ-Ser273 and the metabolic stability in mouse liver microsome assay. To date, there are no published reports on FXR/PPARγ dual partial agonists with biological profiles similar to 18. Thus, the analog would be a feasible candidate as an unprecedented approach to NAFLD associated with type 2 diabetes mellitus.


Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Mice , Animals , PPAR gamma/agonists , Non-alcoholic Fatty Liver Disease/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Transcription Factors , Hypoglycemic Agents/pharmacology
2.
Bioorg Med Chem Lett ; 41: 128026, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33839252

ABSTRACT

Farnesoid X receptor (FXR) controls gene-expression relevant to various diseases including nonalcoholic steatohepatitis and has become a drug target to regulate metabolic aberrations. However, some side effects of FXR agonists reported in clinical development such as an increase in blood cholesterol levels incentivize the development of partial agonists to minimize side effects. In this study, to identify a new partial agonist, we analyzed the computational structure-activity relationship (SAR) of FXR agonists previously developed in our laboratories using molecular dynamics simulations. SAR analysis showed that fluctuations in the H8 helix, by ligand binding, of the ligand-binding domain (LBD) of FXR may influence agonistic activity. Based on this observation, 6 was newly designed as a partial agonist and synthesized. As a result of biological evaluations, 6 showed weak agonistic activity (40.0% relative agonistic activity to the full-agonist GW4064) and a potent EC50 value (55.5 nM). The successful identification of the new potent partial agonist 6 suggested that helix fluctuation in the LBD induced by ligands could be one way to develop partial agonists.


Subject(s)
Chenodeoxycholic Acid/pharmacology , Drug Design , Molecular Dynamics Simulation , Receptors, Cytoplasmic and Nuclear/agonists , Binding Sites/drug effects , Chenodeoxycholic Acid/chemistry , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Structure , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship
3.
ACS Med Chem Lett ; 12(3): 420-425, 2021 Mar 11.
Article in English | MEDLINE | ID: mdl-33738070

ABSTRACT

We describe the discovery of analog 15 (FLG249), which is an orally active and nonsteroidal farnesoid X receptor (FXR) antagonist in mice with unique profiles, such as a propensity for ileum distribution and the significant control in the expression level of three FXR target genes in mouse ileum. Key design features incorporated in 15 were the introduction of metabolically stable groups in potent and metabolically labile antagonist 9. Our pursuit ultimately identified FXR antagonist 15, which has enabled its assessment in a drug discovery program.

4.
Bioorg Med Chem ; 28(14): 115512, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32616182

ABSTRACT

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. With respect to the bone metabolism, FXR positively regulates bone metabolism through both bone formation and resorption of the bone remodeling pathways. Some of FXR agonists possessing isoxazole moiety are undergoing clinical trials for the treatment of non-alcoholic steatohepatitis. To date, therefore, the activation of FXR leads to considerable interest in FXR as potential therapeutic targets. We have identified a series of nonsteroidal FXR agonists bearing N1-methyl benzimidazole and isoxazole moieties that are bridged with aromatic derivatives. They showed affinity to FXR, but also weak affinity toward the vitamin D receptor (VDR) that involves regulation of calcium and phosphate homeostasis and is activated by bile acids. The deployment of FXR agonists without activity against VDR as off-target is therefore crucial in the development of FXR ligands. Our efforts focusing on increasing the agonist properties towards FXR led to the discovery of 19, which activates FXR at and below nanomolar levels (EC50 = 26.5 ± 10.5 nM TR-FRET and 0.8 ± 0.2 nM luciferase, respectively) and functions as a FXR agonist: the affinity toward FXR over eight nuclear receptors, including VDR [IC50 (VDR) / EC50 (FXR) > 5000] and TGR5, effects FXR target genes, and activates bone morphogenetic protein-2-induced differentiation of mouse bone marrow-derived mesenchymal stem cell-like ST2 cells into osteoblast.


Subject(s)
Benzimidazoles/pharmacology , Receptors, Calcitriol/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/agonists , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Receptors, Calcitriol/metabolism , Structure-Activity Relationship
5.
Molecules ; 24(22)2019 Nov 16.
Article in English | MEDLINE | ID: mdl-31744088

ABSTRACT

The modulators of farnesoid X receptor (FXR), a bile acid receptor, regulate various biological processes including bile acid metabolism, and are associated with the control of fatty liver and osteoporosis. Thus, the control of FXR activity and development of FXR modulators are critical not only for research, but also for clinical application. In this study, we synthesized novel FXR agonists 1-4 possessing isoxazole and N-substituted benzimidazole moieties, and compared their effects on osteoblast differentiation with the known FXR agonists, chenodeoxycholic acid and a synthetic compound, GW4064. Two (3 and 4) of the four novel FXR agonists 1-4 showed high specificities for FXR. Computer-assisted modeling suggested that the binding of the FXR agonist 3 with ligand binding domain of FXR was similar to GW4064. FXR was expressed in mouse bone marrow-derived mesenchymal stem cell (MSC)-like ST2 cells (ST-2 MSCs). The FXR agonists activated the BMP-2-induced differentiation of ST-2 MSCs into osteoblasts and enhanced the expression of RUNX2. Moreover, the potency of the FXR agonist 3 was comparable to GW4064 in promoting osteoblast differentiation of ST-2 MSCs. These results indicate that FXR activation enhanced the BMP-2-induced differentiation of MSCs into osteoblasts through activating RUNX2 expression. FXR could be a potential therapeutic target for the treatment of bone diseases such as osteoporosis.


Subject(s)
Cell Differentiation/drug effects , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Osteoblasts/cytology , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Fluoroimmunoassay , Genes, Reporter , Humans , Isoxazoles/chemistry , Mice , Models, Molecular , Receptors, Cytoplasmic and Nuclear/chemistry , Structure-Activity Relationship
6.
Bioorg Med Chem ; 27(11): 2220-2227, 2019 06 01.
Article in English | MEDLINE | ID: mdl-31029550

ABSTRACT

Antagonizing transcriptional activity of farnesoid X receptor (FXR) in the intestine has been reported as an effective means for the treatment of nonalcoholic fatty liver disease, type 2 diabetes and obesity. We describe herein that the building blocks necessary to maintain the antagonism of our chemotype were investigated in order to modulate in vivo pharmacokinetic behavior and the tissue distribution without blunting the activity against FXR. A comprehensive understanding of the structure-activity relationship led to analog 30, which is superior to 12 in terms of its pharmacokinetic profiles by oral administration and its tissue distribution toward target tissues (liver and ileum) in rats while preserving the in vitro activity of 12 against FXR. Thus, 30 should be a candidate compound to investigate the effects of inhibiting FXR activity while simultaneously improving the outcome of nonalcoholic fatty liver disease, type 2 diabetes and obesity.


Subject(s)
Benzimidazoles/pharmacokinetics , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Administration, Intravenous , Administration, Oral , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Benzimidazoles/administration & dosage , Benzimidazoles/chemical synthesis , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Ileum/metabolism , Liver/metabolism , Male , Molecular Structure , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
ACS Med Chem Lett ; 9(2): 78-83, 2018 Feb 08.
Article in English | MEDLINE | ID: mdl-29456791

ABSTRACT

Farnesoid X receptor (FXR) plays a major role in the control of cholesterol metabolism. Antagonizing transcriptional activity of FXR is an effective means to treat the relevant metabolic syndrome. Some of antagonists so far have the charged functions; however, they may negatively affect the pharmacokinetics. We describe herein a structure-activity relationship (SAR) exploration of nonacidic FXR antagonist 6 focusing on two regions in the structure and biological evaluation of nonacidic 10 with the characteristic N-acylated piperidine group obtained from SAR studies. As the robust affinity to FXR is feasible with our nonacidic analogue, 10 is among the most promising candidates for in vivo testing.

8.
Bioorg Med Chem ; 25(6): 1787-1794, 2017 03 15.
Article in English | MEDLINE | ID: mdl-28190654

ABSTRACT

We describe here a novel chemotype with substituted benzimidazole scaffold for nonsteroidal farnesoid X receptor (FXR) antagonists starting from the identification of a screening hit, BB-4. Structure diversity in four regions A-D of BB-4 or 1 is discussed. In particular, regions A and C had an effect on an antagonism against FXR as demonstrated by the derivatives represented by 7 and 15, respectively. Thus, compound 19 arising from the combination of regions A and C underscored an important fact on antagonism against FXR, also showing the reduced small heterodimer partner and the increased cholesterol 7α-hydroxylase expression levels.


Subject(s)
Benzimidazoles/pharmacology , Drug Discovery , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Benzimidazoles/chemistry , Cell Line, Tumor , Cholesterol 7-alpha-Hydroxylase/genetics , Cholesterol 7-alpha-Hydroxylase/metabolism , Fluorescence Resonance Energy Transfer , Humans , Proton Magnetic Resonance Spectroscopy , RNA, Messenger/genetics , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 26(9): 2259-61, 2016 May 01.
Article in English | MEDLINE | ID: mdl-27009905

ABSTRACT

In this letter we report the design and synthesis of a series of plasmin inhibitors, which share the amino acid-based linker with limited free rotation between the hydantoin moiety and the benzimidazole scaffold. Our studies led to potent plasmin inhibitors and yielded important new insights into their structure-activity relationship for binding to the active site of plasmin.


Subject(s)
Amino Acids/chemistry , Benzimidazoles/pharmacology , Fibrinolysin/antagonists & inhibitors , Hydantoins/chemistry , Benzimidazoles/chemistry , Hydrophobic and Hydrophilic Interactions
10.
Bioorg Med Chem ; 24(4): 545-53, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26732532

ABSTRACT

Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert-butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O-(quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77µM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site.


Subject(s)
Antifibrinolytic Agents/pharmacology , Fibrinolysin/antagonists & inhibitors , Fibrinolysin/chemistry , Antifibrinolytic Agents/chemical synthesis , Antifibrinolytic Agents/chemistry , Catalytic Domain/drug effects , Dose-Response Relationship, Drug , Fibrinolysin/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Tyrosine/antagonists & inhibitors , Tyrosine/metabolism , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Urokinase-Type Plasminogen Activator/metabolism
11.
Bioorg Med Chem ; 23(13): 3696-704, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25921265

ABSTRACT

Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin.


Subject(s)
Antifibrinolytic Agents/chemistry , Fibrinolysin/antagonists & inhibitors , Fibrinolytic Agents/chemistry , Pyrimidines/chemistry , Pyrroles/chemistry , Antifibrinolytic Agents/chemical synthesis , Benzimidazoles/chemistry , Catalytic Domain , Fibrinolysin/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Structure-Activity Relationship
12.
Bioorg Med Chem ; 22(7): 2339-52, 2014 Apr 01.
Article in English | MEDLINE | ID: mdl-24613052

ABSTRACT

In the development of plasmin inhibitors, a novel chemotype, pyrrolopyrimidine scaffold possessing two motifs, a hydantoin-containing P4 moiety and a warhead-containing P1 moiety, is uncovered. A unique feature of the new line of the plasmin inhibitors is that the interaction between the plasmin inhibitors and key subsites in plasmin can be controlled by a spacer like hydantoin. The application of the novel chemotype is demonstrated by 1n and provides further evidence on the importance of hydantoin as the spacer.


Subject(s)
Antifibrinolytic Agents/pharmacology , Fibrinolysin/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Antifibrinolytic Agents/chemical synthesis , Antifibrinolytic Agents/chemistry , Dose-Response Relationship, Drug , Fibrinolysin/metabolism , Models, Molecular , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship
13.
Chem Biol Drug Des ; 83(1): 52-7, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24112688

ABSTRACT

We here strove to overcome the limitations of expression analyses such as PCR and IHC, based on molecular recognition between target and probe molecules, by designing synthetic substrates specific to the target molecules to directly estimate the enzymatic functionality in situ. The specific substrate contains a probing unit, which is an organic fragment for specific enzyme binding, and a reactive unit, which is a natural peptide subject to catalysis. In this study, the activation of plasminogen to plasmin was examined in MDA-MB231 breast cancer cells using the plasmin-specific synthetic substrates designed from their inhibitors. The localization and function of the activated plasmin were successfully visualized by fluorophore combined with the specific substrate concurrently. This would be the first time for activated plasmin at work in situ by direct observation. Our concept to directly monitor the functionality of target enzymes can be used straightforwardly for other proteases such as cathepsins or caspases. Also, this substrate concept as a 'tailor-made substrate' would be utilized as a novel functional molecular probe in vivo with appropriate detectable probes.


Subject(s)
Fibrinolysin/metabolism , Protease Inhibitors/chemical synthesis , Binding Sites , Breast Neoplasms/enzymology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Fibrinolysin/antagonists & inhibitors , Fluorescent Dyes/chemistry , Humans , Kinetics , Microscopy, Confocal , Molecular Docking Simulation , Plasminogen/metabolism , Protease Inhibitors/metabolism , Protein Binding , Protein Structure, Tertiary , Substrate Specificity
14.
Org Lett ; 15(7): 1560-3, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-23496249

ABSTRACT

Metal-catalyzed reactions of ynimides with alcohols to afford ß-ketoimides and oxazoles are demonstrated. The triple bond of ynamides is generally activated by mineral acids or metal salts to lead to the regioselective addition of nucleophiles at the α-C-atom, because of the inherent electronic bias. In contrast, the two neighboring carbonyl groups of ynimides decrease the electron density of the triple bond and the nucleophiles attack the carbonyl C-atom.


Subject(s)
Alcohols/chemistry , Gold/chemistry , Imides/chemistry , Oxazoles/chemical synthesis , Silver/chemistry , Catalysis , Imides/chemical synthesis , Molecular Structure , Oxazoles/chemistry , Stereoisomerism
15.
J Pept Sci ; 18(10): 620-5, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22961872

ABSTRACT

Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC(50) = 7.7-11 µM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin.


Subject(s)
Fibrinolysin/antagonists & inhibitors , Nitriles/chemistry , Oligopeptides/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Plasma Kallikrein/antagonists & inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Urokinase-Type Plasminogen Activator/antagonists & inhibitors
16.
J Enzyme Inhib Med Chem ; 27(4): 571-7, 2012 Aug.
Article in English | MEDLINE | ID: mdl-21992704

ABSTRACT

Plasmin plays important roles in various physiological systems. The identification of inhibitors controlling its regulation represents a promising drug-discovery challenge. To develop selective inhibitors of plasmin, structural information of the binding modes is crucial. Here, a computational docking study was conducted to provide structural insight into plasmin subsite interactions with substrates/inhibitors. Predicted binding modes of two peptide-substrates (D/L-Ile-Phe-Lys), and potent and weak inhibitors (YO-2 and PKSI-527) suggested non-prime and prime subsite interactions relevant to recognition by plasmin. Predicted binding modes also correlated well with the experimental structure-activity relationships for plasmin substrates/inhibitors, namely the differences of K(M) values between the D- and L-peptide-substrates and inhibitory potencies of YO-2 and PKSI-527. In particular, interaction observed at a hydrophobic pocket near S2 and at a tunnel-shaped hydrophobic S1' was strongly suggested to be significantly involved in tight binding of inhibitors to plasmin. Our present findings may aid in the design of potent and selective plasmin inhibitors.


Subject(s)
Computational Biology , Fibrinolysin/antagonists & inhibitors , Oligopeptides/pharmacology , Serine Proteinase Inhibitors/pharmacology , Dipeptides/chemistry , Dipeptides/pharmacology , Dose-Response Relationship, Drug , Fibrinolysin/chemistry , Fibrinolysin/metabolism , Models, Molecular , Molecular Structure , Oligopeptides/chemistry , Phenylalanine/analogs & derivatives , Phenylalanine/chemistry , Phenylalanine/pharmacology , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Substrate Specificity , Tranexamic Acid/analogs & derivatives , Tranexamic Acid/chemistry , Tranexamic Acid/pharmacology
17.
Bioorg Med Chem Lett ; 21(21): 6305-9, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21944858

ABSTRACT

Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9.


Subject(s)
Fibrinolysin/antagonists & inhibitors , Nitriles/chemistry , Models, Molecular
18.
Org Lett ; 13(15): 3996-9, 2011 Aug 05.
Article in English | MEDLINE | ID: mdl-21710984

ABSTRACT

This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group.


Subject(s)
Imides/chemical synthesis , Alkylation , Catalysis , Copper/chemistry , Molecular Structure
20.
Expert Opin Ther Pat ; 20(4): 563-82, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20302452

ABSTRACT

IMPORTANCE OF THE FIELD: Bones play many roles in the body, providing structure, protecting organs, anchoring muscles and storing calcium. Over 100 million people worldwide suffer from bone diseases, mainly osteoporosis, cancer-related bone loss, osteoarthritis and inflammatory arthritis. Osteoporosis itself has no specific symptoms, and the main consequence is the increased risk of bone fractures. Therefore, the prevention of bone diseases is important to maintain the quality of life in the human society. However, treatment options are still insufficient. AREAS COVERED IN THIS REVIEW: This review article gives a summary of the low molecular mass modulators of bone diseases targets disclosed in patent applications and articles, mainly during the last 5 years. WHAT THE READER WILL GAIN: Readers will rapidly gain an overview of these modulators not only for historical targets, but also of emerging and re-visited targets. Readers will also be able to see the current research trend and the main players in this field. TAKE HOME MESSAGE: Drug discovery for bone diseases has made progress in the last years. The research area has dynamically shifted from historical targets (bisphosphonate, parathyroid hormone and calcitonin) to newly confirmed targets or targets re-visited which were biologically validated in the past. Cathepsin K inhibitors should be very close to launching in the market.


Subject(s)
Bone Diseases/drug therapy , Drug Delivery Systems , Drug Design , Animals , Bone Diseases/physiopathology , Drug Discovery/methods , Humans , Patents as Topic , Quality of Life
SELECTION OF CITATIONS
SEARCH DETAIL
...