Page last updated: 2024-11-13

mna 715

Description Research Excerpts Clinical Trials Roles Classes Pathways Study Profile Bioassays Related Drugs Related Conditions Protein Interactions Research Growth Market Indicators

Description

2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide: structure in first source; a derivative of A77 1726, the active metabolite of the antirheumatic drug leflunomide, where the isoxazole ring has opened to become a nitrile and an alkyne [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID Source	ID
PubMed CID	54686843
CHEMBL ID	4754445
MeSH ID	M0269242

Synonyms (31)

Synonym
manitimus
fk-778
hmr-1715
x-920715
mna-715
fk 778
malononitrilamide 715
2-cyano-3-hydroxy-n-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide
mna 715
x 920715
mna-x 920715
185915-33-7
malononitrilamide-715
2-hepten-6-ynamide, 2-cyano-3-hydroxy-n-(4-(trifluoromethyl)phenyl)-, (z)-
2-cyano-3-hydroxy-n-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynoic acid
unii-4b135rk2kl
4b135rk2kl ,
(2z)-2-cyano-3-hydroxy-n-(4-(trifluoromethyl)phenyl)hept-2-en-6-ynamide
2-hepten-6-ynamide, 2-cyano-3-hydroxy-n-(4-(trifluoromethyl)phenyl)-
manitimus [inn]
202057-76-9
hmr1715
(2z)-2-cyano-3-hydroxy-n-(4-(trifluoromethly)phenyl)-2-hepten-6-ynamide
hmr-1715 [who-dd]
DB06481
Q27259358
(z)-2-cyano-3-hydroxy-n-[4-(trifluoromethyl)phenyl]hept-2-en-6-ynamide
BM162377
irelroqhiplasx-seyxrhqnsa-n
CHEMBL4754445
AKOS040733665

Research Excerpts

Toxicity

Excerpt	Reference	Relevance
" A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation."	( Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy. First, MR; Fitzsimmons, W; Guasch, A; Holman, J; Roy-Chaudhury, P; Woodle, ES, 2010)	0.36
" Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression."	( Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy. First, MR; Fitzsimmons, W; Guasch, A; Holman, J; Roy-Chaudhury, P; Woodle, ES, 2010)	0.36

Compound-Compound Interactions

Excerpt	Reference	Relevance
"In a double-blind manner, 149 patients were randomized to a 12-week treatment with FK778 in combination with tacrolimus (Tac) and corticosteroids (S)."	( The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients. Chang, R; Charpentier, B; Grinyó, JM; Jurewicz, A; Klinger, M; Kreis, H; Mourad, G; Neuhaus, P; Paczek, L; Paul, LC; Rostaing, L; Short, C; Squifflet, JP; van Hooff, JP; Vanrenterghem, Y; Wlodarczyk, Z, 2004)	0.32
"We evaluated the in vitro capacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of T-lymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite."	( Role of FK778 alone or in combination with tacrolimus or mTOR inhibitors as an immunomodulator of immunofunctions: in vitro evaluation of T cell proliferation and the expression of lymphocyte surface antigens. Barceló, JJ; Brunet, M; Fortuna, V; Jiménez, O; Millán, O, )	0.13

Dosage Studied

Excerpt	Relevance	Reference
" At doses lower than 10 mg/kg daily, FK778 is cleared from the circulation between the dosing intervals, thus failing to exert its inhibitory effects on immune functions."	( In vivo pharmacokinetic and pharmacodynamic evaluation of the malononitrilamide FK778 in non-human primates. Bîrsan, T; Dambrin, C; Fitzsimmons, WE; Klupp, J; Larson, MJ; Morris, RE; Stalder, M, 2003)	0.32
" Research and development programs are underway for a new modified release dosage form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several novel compounds (PG 490-88, AGI 1096) in collaboration with other companies."	( New drugs to improve transplant outcomes. First, MR; Fitzsimmons, WE, 2004)	0.32
" To fully benefit from this promising new drug, FK778 dosing will be optimized in subsequent studies."	( The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients. Chang, R; Charpentier, B; Grinyó, JM; Jurewicz, A; Klinger, M; Kreis, H; Mourad, G; Neuhaus, P; Paczek, L; Paul, LC; Rostaing, L; Short, C; Squifflet, JP; van Hooff, JP; Vanrenterghem, Y; Wlodarczyk, Z, 2004)	0.32
" The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day."	( FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation. Hirohashi, K; Ikeda, K; Kubo, S; Minamiyama, Y; Okuda, T; Suehiro, S; Takemura, S; Tanaka, H; Yamamoto, S; Yamasaki, K, 2004)	0.32
"05) or 1 day after angioplasty in both dosage groups (group 1b, P<."	( 2005 Dr. Gary J. Becker Young Investigator Award: periprocedural oral administration of the leflunomide analogue FK778 inhibits neointima formation in a double-injury rat model of restenosis. Bolte, H; Brossmann, J; Fändrich, F; Hedderich, J; Heller, M; Jahnke, T; Müller-Hülsbeck, S; Rector, L; Schäfer, FK; Schäfer, PJ, 2005)	0.33
" In addition, FK778 also reduced the levels of preformed circulating autoantibodies in adult mice, although the dosage required was 4 times higher than that used in neonates."	( Leflunomide derivative FK778 inhibits production of antibodies in an experimental model of alloreactive T-B cell interaction. Agüeros, C; Arias, M; Benito, A; Cosme, LS; Gimenez, T; Gómez-Alamillo, C; Merino, J; Merino, R; Ramos-Barrón, MA; Santiuste, I, 2009)	0.35

[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (87)

Timeframe	Studies, This Drug (%)	All Drugs %
pre-1990	0 (0.00)	18.7374
1990's	36 (41.38)	18.2507
2000's	47 (54.02)	29.6817
2010's	4 (4.60)	24.3611
2020's	0 (0.00)	2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 9.61

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be weak demand-to-supply ratio for research on this compound.

Metric	This Compound (vs All)
Research Demand Index	9.61 (24.57)
Research Supply Index	4.68 (2.92)
Research Growth Index	4.29 (4.65)
Search Engine Demand Index	0.00 (26.88)
Search Engine Supply Index	0.00 (0.95)

This Compound (9.61)

All Compounds (24.57)

Study Types

Publication Type	This drug (%)	All Drugs (%)
Trials	3 (2.88%)	5.53%
Reviews	6 (5.77%)	6.00%
Case Studies	0 (0.00%)	4.05%
Observational	0 (0.00%)	0.25%
Other	95 (91.35%)	84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Substance	Relationship Strength	Studies	Trials	Classes	Roles
leflunomide Leflunomide: An isoxazole derivative that inhibits dihydroorotate dehydrogenase, the fourth enzyme in the pyrimidine biosynthetic pathway. It is used an immunosuppressive agent in the treatment of RHEUMATOID ARTHRITIS and PSORIATIC ARTHRITIS.. leflunomide : A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-methyl-1,2-oxazole-4-carboxylic acid with the anilino group of 4-(trifluoromethyl)aniline. The prodrug of teriflunomide.	4.63	10	0	(trifluoromethyl)benzenes; isoxazoles; monocarboxylic acid amide	antineoplastic agent; antiparasitic agent; EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor; EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor; hepatotoxic agent; immunosuppressive agent; non-steroidal anti-inflammatory drug; prodrug; pyrimidine synthesis inhibitor; tyrosine kinase inhibitor
probucol Probucol: A drug used to lower LDL and HDL cholesterol yet has little effect on serum-triglyceride or VLDL cholesterol. (From Martindale, The Extra Pharmacopoeia, 30th ed, p993).. probucol : A dithioketal that is propane-2,2-dithiol in which the hydrogens attached to both sulfur atoms are replaced by 3,5-di-tert-butyl-4-hydroxyphenyl groups. An anticholesteremic drug with antioxidant and anti-inflammatory properties, it is used to treat high levels of cholesterol in blood.	3.12	1	0	dithioketal; polyphenol	anti-inflammatory drug; anticholesteremic drug; antilipemic drug; antioxidant; cardiovascular drug
prednisolone Prednisolone: A glucocorticoid with the general properties of the corticosteroids. It is the drug of choice for all conditions in which routine systemic corticosteroid therapy is indicated, except adrenal deficiency states.. prednisolone : A glucocorticoid that is prednisone in which the oxo group at position 11 has been reduced to the corresponding beta-hydroxy group. It is a drug metabolite of prednisone.	3.4	1	1	11beta-hydroxy steroid; 17alpha-hydroxy steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(1),Delta(4)-steroid; C21-steroid; glucocorticoid; primary alpha-hydroxy ketone; tertiary alpha-hydroxy ketone	adrenergic agent; anti-inflammatory drug; antineoplastic agent; drug metabolite; environmental contaminant; immunosuppressive agent; xenobiotic
uridine [no description available]	3.4	7	0	uridines	drug metabolite; fundamental metabolite; human metabolite
acrylamide [no description available]	2.91	4	0	acrylamides; N-acylammonia; primary carboxamide	alkylating agent; carcinogenic agent; Maillard reaction product; mutagen; neurotoxin
isoxazoles Isoxazoles: Azoles with an OXYGEN and a NITROGEN next to each other at the 1,2 positions, in contrast to OXAZOLES that have nitrogens at the 1,3 positions.. isoxazole : A monocyclic heteroarene with a structure consisting of a 5-membered ring containing three carbon atoms and an oxygen and nitrogen atom adjacent to each other. It is the parent of the class of isoxazoles.. isoxazoles : Oxazoles in which the N and O atoms are adjacent.	11.41	87	3	isoxazoles; mancude organic heteromonocyclic parent; monocyclic heteroarene
brequinar brequinar : A quinolinemonocarboxylic acid that is quinoline substituted by 2'-fluoro[1,1'-biphenyl]-4-yl, methyl, carboxy and fluoro groups at positions 2, 3, 4, and 6, respectively. It is an inhibitor of dihydroorotate dehydrogenase, an enzyme that is required for de novo pyrimidine biosynthesis. The compound exhibits antineoplastic and antiviral properties.	2	1	0	biphenyls; monocarboxylic acid; monofluorobenzenes; quinolinemonocarboxylic acid	anticoronaviral agent; antimetabolite; antineoplastic agent; antiviral agent; EC 1.3.5.2 [dihydroorotate dehydrogenase (quinone)] inhibitor; immunosuppressive agent; pyrimidine synthesis inhibitor
triptolide [no description available]	3.12	1	0	diterpenoid; epoxide; gamma-lactam; organic heteroheptacyclic compound	antispermatogenic agent; plant metabolite
imatinib mesylate imatinib methanesulfonate : A methanesulfonate (mesylate) salt that is the monomesylate salt of imatinib. Used for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours.	2.01	1	0	methanesulfonate salt	anticoronaviral agent; antineoplastic agent; apoptosis inducer; tyrosine kinase inhibitor
tacrolimus Tacrolimus: A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.. tacrolimus (anhydrous) : A macrolide lactam containing a 23-membered lactone ring, originally isolated from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.	7.77	20	3	macrolide lactam	bacterial metabolite; immunosuppressive agent
mycophenolic acid Mycophenolic Acid: Compound derived from Penicillium stoloniferum and related species. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase (IMP DEHYDROGENASE). Mycophenolic acid exerts selective effects on the immune system in which it prevents the proliferation of T-CELLS, LYMPHOCYTES, and the formation of antibodies from B-CELLS. It may also inhibit recruitment of LEUKOCYTES to sites of INFLAMMATION.. mycophenolate : A monocarboxylic acid anion resulting from the removal of a proton from the carboxy group of mycophenolic acid.. mycophenolic acid : A member of the class of 2-benzofurans that is 2-benzofuran-1(3H)-one which is substituted at positions 4, 5, 6, and 7 by methyl, methoxy, (2E)-5-carboxy-3-methylpent-2-en-1-yl, and hydroxy groups, respectively. It is an antibiotic produced by Penicillium brevi-compactum, P. stoloniferum, P. echinulatum and related species. An immunosuppressant, it is widely used (partiularly as its sodium salt and as the 2-(morpholin-4-yl)ethyl ester prodrug, mycophenolate mofetil) to prevent tissue rejection following organ transplants and for the treatment of certain autoimmune diseases.	6.15	6	2	2-benzofurans; gamma-lactone; monocarboxylic acid; phenols	anticoronaviral agent; antimicrobial agent; antineoplastic agent; EC 1.1.1.205 (IMP dehydrogenase) inhibitor; environmental contaminant; immunosuppressive agent; mycotoxin; Penicillium metabolite; xenobiotic
sirolimus Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.. sirolimus : A macrolide lactam isolated from Streptomyces hygroscopicus consisting of a 29-membered ring containing 4 trans double bonds, three of which are conjugated. It is an antibiotic, immunosupressive and antineoplastic agent.	4.52	5	1	antibiotic antifungal drug; cyclic acetal; cyclic ketone; ether; macrolide lactam; organic heterotricyclic compound; secondary alcohol	antibacterial drug; anticoronaviral agent; antineoplastic agent; bacterial metabolite; geroprotector; immunosuppressive agent; mTOR inhibitor
mna 279 HMR 279: a leflunomide analog; structure in first source	5.89	32	0
teriflunomide [no description available]	4.19	5	0	(trifluoromethyl)benzenes; aromatic amide; enamide; enol; nitrile; secondary carboxamide	drug metabolite; EC 1.3.98.1 [dihydroorotate oxidase (fumarate)] inhibitor; hepatotoxic agent; non-steroidal anti-inflammatory drug; tyrosine kinase inhibitor
transforming growth factor beta Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins.	3.13	5	0
cyclosporine Cyclosporine: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).	10.74	20	1
phenanthrenes Phenanthrenes: POLYCYCLIC AROMATIC HYDROCARBONS composed of three fused BENZENE rings.. phenanthrenes : Any benzenoid aromatic compound that consists of a phenanthrene skeleton and its substituted derivatives thereof.	3.12	1	0

Condition	Relationship Strength	Studies	Trials
Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	3.96	13	0
Kidney Diseases Pathological processes of the KIDNEY or its component tissues.	2.45	2	0
B Virus Infection [description not available]	2.05	1	0
Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells.	2.73	3	0
Aging The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.	2.7	3	0
Injury, Ischemia-Reperfusion [description not available]	2.05	1	0
Reperfusion Injury Adverse functional, metabolic, or structural changes in tissues that result from the restoration of blood flow to the tissue (REPERFUSION) following ISCHEMIA.	2.05	1	0
Polyomavirus Infections Infections with POLYOMAVIRUS, which are often cultured from the urine of kidney transplant patients. Excretion of BK VIRUS is associated with ureteral strictures and CYSTITIS, and that of JC VIRUS with progressive multifocal leukoencephalopathy (LEUKOENCEPHALOPATHY, PROGRESSIVE MULTIFOCAL).	3.44	1	1
Sensitivity and Specificity Binary classification measures to assess test results. Sensitivity or recall rate is the proportion of true positives. Specificity is the probability of correctly determining the absence of a condition. (From Last, Dictionary of Epidemiology, 2d ed)	2.99	1	0
Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms.	2.42	2	0
Acute Disease Disease having a short and relatively severe course.	5.26	12	1
Recrudescence [description not available]	2.41	2	0
Constriction, Pathological [description not available]	2.01	1	0
Constriction, Pathologic The condition of an anatomical structure's being constricted beyond normal dimensions.	2.01	1	0
Vascular Diseases Pathological processes involving any of the BLOOD VESSELS in the cardiac or peripheral circulation. They include diseases of ARTERIES; VEINS; and rest of the vasculature system in the body.	2.01	1	0
Cytomegalovirus A genus of the family HERPESVIRIDAE, subfamily BETAHERPESVIRINAE, infecting the salivary glands, liver, spleen, lungs, eyes, and other organs, in which they produce characteristically enlarged cells with intranuclear inclusions. Infection with Cytomegalovirus is also seen as an opportunistic infection in AIDS.	2.02	1	0
Cytomegalic Inclusion Disease [description not available]	2.02	1	0
Cytomegalovirus Infections Infection with CYTOMEGALOVIRUS, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults.	2.02	1	0
Bronchiolitis, Exudative [description not available]	2.02	1	0
Complication, Postoperative [description not available]	2.02	1	0
Bronchiolitis Obliterans Inflammation of the BRONCHIOLES leading to an obstructive lung disease. Bronchioles are characterized by fibrous granulation tissue with bronchial exudates in the lumens. Clinical features include a nonproductive cough and DYSPNEA.	2.02	1	0
Postoperative Complications Pathologic processes that affect patients after a surgical procedure. They may or may not be related to the disease for which the surgery was done, and they may or may not be direct results of the surgery.	2.02	1	0
Obstructive Lung Diseases [description not available]	2.03	1	0
Lung Diseases, Obstructive Any disorder marked by obstruction of conducting airways of the lung. AIRWAY OBSTRUCTION may be acute, chronic, intermittent, or persistent.	2.03	1	0
Graft Occlusion, Vascular Obstruction of flow in biological or prosthetic vascular grafts.	2.03	1	0
Chronic Illness [description not available]	2.93	4	0
Chronic Disease Diseases which have one or more of the following characteristics: they are permanent, leave residual disability, are caused by nonreversible pathological alteration, require special training of the patient for rehabilitation, or may be expected to require a long period of supervision, observation, or care (Dictionary of Health Services Management, 2d ed). For epidemiological studies chronic disease often includes HEART DISEASES; STROKE; CANCER; and diabetes (DIABETES MELLITUS, TYPE 2).	2.93	4	0
Disease Exacerbation [description not available]	2.03	1	0
Proteinuria The presence of proteins in the urine, an indicator of KIDNEY DISEASES.	2.03	1	0
Aortic Diseases Pathological processes involving any part of the AORTA.	2.04	1	0
Graft-Versus-Host Disease [description not available]	4.29	7	0
Libman-Sacks Disease [description not available]	3.09	5	0
Graft vs Host Disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the GRAFT VS HOST REACTION.	4.29	7	0
Lupus Erythematosus, Systemic A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys, and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.	3.09	5	0
Enlarged Spleen [description not available]	2.39	2	0
Allergic Encephalomyelitis [description not available]	2.4	2	0
Autoimmune Disease [description not available]	3.6	3	0
Autoimmune Diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides.	3.6	3	0
Adjuvant Arthritis [description not available]	2.4	2	0
Rheumatoid Arthritis [description not available]	2.4	2	0
Arthritis, Rheumatoid A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.	2.4	2	0
Bright Disease A historical classification which is no longer used. It described acute glomerulonephritis, acute nephritic syndrome, or acute nephritis. Named for Richard Bright.	1.99	1	0
Glomerulonephritis Inflammation of the renal glomeruli (KIDNEY GLOMERULUS) that can be classified by the type of glomerular injuries including antibody deposition, complement activation, cellular proliferation, and glomerulosclerosis. These structural and functional abnormalities usually lead to HEMATURIA; PROTEINURIA; HYPERTENSION; and RENAL INSUFFICIENCY.	1.99	1	0
Autoimmune Diabetes [description not available]	2.41	2	0
Diabetes Mellitus, Type 1 A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence.	2.41	2	0
Weight Reduction [description not available]	2	1	0
Weight Gain Increase in BODY WEIGHT over existing weight.	2	1	0
Weight Loss Decrease in existing BODY WEIGHT.	2	1	0

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