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{{short description|Chemical compound}} |
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{{drugbox |
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{{drugbox |
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| Verifiedfields = changed |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = K7G81N94DT |
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| UNII = K7G81N94DT |
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| verifiedrevid = 443468360 |
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| verifiedrevid = 444359019 |
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| IUPAC_name = ''N''-(1-{3-propyl}-4-phenylpiperidin-4-yl]-''N''-methylacetamide |
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| IUPAC_name = ''N''-(1-{3-propyl}-4-phenylpiperidin-4-yl]-''N''-methylacetamide |
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| image = Osanetant.png |
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| image = Osanetant.png |
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| width = 220 |
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| width = 220 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 160492-56-8 |
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| CAS_number = 160492-56-8 |
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| CAS_supplemental = |
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| CAS_supplemental = |
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| ATC_prefix = none |
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| ATC_prefix = none |
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| ATC_suffix = |
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| ATC_suffix = |
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| PubChem = 219077 |
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| PubChem = 219077 |
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| IUPHAR_ligand = 2110 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| DrugBank = |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 346178 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 189901 |
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| C=35|H=41|Cl=2|N=3|O=2 |
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| C=35|H=41|Cl=2|N=3|O=2 |
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| smiles = CC(=O)N(C)C1(CCN(CC1)CCC2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5 |
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| molecular_weight = 606.625 g/mol |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| smiles = CC(=O)N(C)C1(CCN(CC1)CCC2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5 |
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| StdInChI = 1S/C35H41Cl2N3O2/c1-27(41)38(2)35(29-13-7-4-8-14-29)19-23-39(24-20-35)21-9-17-34(30-15-16-31(36)32(37)25-30)18-10-22-40(26-34)33(42)28-11-5-3-6-12-28/h3-8,11-16,25H,9-10,17-24,26H2,1-2H3/t34-/m0/s1 |
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| bioavailability = |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| protein_bound = |
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| StdInChIKey = DZOJBGLFWINFBF-UMSFTDKQSA-N |
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| metabolism = |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| elimination_half-life = |
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| excretion = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = |
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| pregnancy_US = |
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| pregnancy_category= |
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| pregnancy_category= |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US = |
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| legal_US = |
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| routes_of_administration = |
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| routes_of_administration = |
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}} |
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}} |
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'''Osanetant''' ('''SR-142,801''') is a ] receptor antagonist developed by ], which is being researched for the treatment of ].<ref>{{cite journal | pmid = 11757797 | volume=2 | issue=7 | title=Osanetant Sanofi-Synthélabo | year=2001 | month=July | pages=950–6 | last1 = Kamali | first1 = F | journal = Current opinion in investigational drugs (London, England : 2000)}}</ref> It was the first non-peptide NK<sub>3</sub> antagonist developed in the mid-1990s,<ref>{{cite journal | pmid = 7830490 | volume=56 | issue=1 | title=SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor | year=1995 | pages=PL27–32 | last1 = Emonds-Alt | first1 = X | last2 = Bichon | first2 = D | last3 = Ducoux | first3 = JP | last4 = Heaulme | first4 = M | last5 = Miloux | first5 = B | last6 = Poncelet | first6 = M | last7 = Proietto | first7 = V | last8 = Van Broeck | first8 = D | last9 = Vilain | first9 = P | journal = Life sciences}}</ref> and has still not made it to market, although clinical trials are continuing.<ref name="pmid16918326">{{cite journal | author = Quartara L, Altamura M | title = Tachykinin receptors antagonists: from research to clinic | journal = Current Drug Targets | volume = 7 | issue = 8 | pages = 975–92 | year = 2006 | month = August | pmid = 16918326 | doi = 10.2174/138945006778019381| url = http://www.benthamdirect.org/pages/content.php?CDT/2006/00000007/00000008/0007J.SGM | issn = | accessdate = 2011-04-14}}</ref> Another potential application for osanetant is in the treatment of ], as it has been found to block the effects of ] in animal models.<ref>{{cite journal | pmid = 16603151 | doi=10.1016/j.ejphar.2006.03.010 | volume=536 | issue=3 | title=The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys | year=2006 | month=May | pages=269–78 | last1 = Desouzasilva | first1 = M | last2 = Mellojr | first2 = E | last3 = Muller | first3 = C | last4 = Jocham | first4 = G | last5 = Maior | first5 = R | last6 = Huston | first6 = J | last7 = Tomaz | first7 = C | last8 = Barros | first8 = M | journal = European Journal of Pharmacology}}</ref><ref>{{cite journal | pmid = 17004936 | doi=10.1111/j.1460-9568.2006.05041.x | volume=24 | issue=6 | title=Neurokinin receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core | year=2006 | month=September | pages=1721–32 | last1 = Jocham | first1 = Gerhard | last2 = Lezoch | first2 = Katharina | last3 = Müller | first3 = Christian P. | last4 = Kart-Teke | first4 = Emriye | last5 = Huston | first5 = Joseph P. | last6 = De Souza Silva | first6 = M. AngéLica | journal = European Journal of Neuroscience}}</ref> |
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'''Osanetant''' (developmental code name '''SR-142,801''') is a ] ] which was developed by ] and was being researched for the treatment of ] but was discontinued.<ref>{{cite web|title=osanetant Sanofi-Aventis discontinued, France.|url=http://business.highbeam.com/436989/article-1G1-135970821/osanetant-sanofiaventis-discontinued-france|archive-url=https://web.archive.org/web/20160311183306/https://business.highbeam.com/436989/article-1G1-135970821/osanetant-sanofiaventis-discontinued-france|url-status=dead|archive-date=2016-03-11|publisher=Highbeam}}</ref><ref>{{cite journal | vauthors = Kamali F | title = Osanetant Sanofi-Synthélabo | journal = Current Opinion in Investigational Drugs | volume = 2 | issue = 7 | pages = 950–956 | date = July 2001 | pmid = 11757797 }}</ref> It was the first non-peptide NK<sub>3</sub> antagonist developed in the mid-1990s.<ref>{{cite journal | vauthors = Emonds-Alt X, Bichon D, Ducoux JP, Heaulme M, Miloux B, Poncelet M, Proietto V, Van Broeck D, Vilain P, Neliat G | display-authors = 6 | title = SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor | journal = Life Sciences | volume = 56 | issue = 1 | pages = PL27–PL32 | year = 1995 | pmid = 7830490 | doi = 10.1016/0024-3205(94)00413-M }}</ref><ref name="pmid16918326">{{cite journal | vauthors = Quartara L, Altamura M | title = Tachykinin receptors antagonists: from research to clinic | journal = Current Drug Targets | volume = 7 | issue = 8 | pages = 975–992 | date = August 2006 | pmid = 16918326 | doi = 10.2174/138945006778019381 | url = http://www.benthamdirect.org/pages/content.php?CDT/2006/00000007/00000008/0007J.SGM | url-status = dead | archive-url = https://web.archive.org/web/20110725065700/http://www.benthamdirect.org/pages/content.php?CDT%2F2006%2F00000007%2F00000008%2F0007J.SGM | archive-date = 2011-07-25 }}</ref> |
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Professor David J. Anderson, Director and Leadership Chair of the Tianqiao and Chrissy Chen Institute for Neuroscience at California Institute of Technology, has advocated that osanetant be explored as a treatment for pain, anxiety, and aggression in humans and companion animals experiencing bereavement or social isolation, citing research suggesting that osanetant has an excellent safety profile and suppresses negative effects of social isolation in mice through an evolutionarily-conserved mechanism and without acting as a depressant.<ref>{{Cite web | vauthors = Huberman A |date=2022-09-12 |title=Dr. David Anderson: The Biology of Aggression, Mating & Arousal |url=https://hubermanlab.com/dr-david-anderson-the-biology-of-aggression-mating-and-arousal/ |access-date=2022-10-23 |website=Huberman Lab |language=en-US}}</ref><ref>{{cite journal | vauthors = Zelikowsky M, Hui M, Karigo T, Choe A, Yang B, Blanco MR, Beadle K, Gradinaru V, Deverman BE, Anderson DJ | display-authors = 6 | title = The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress | journal = Cell | volume = 173 | issue = 5 | pages = 1265–1279.e19 | date = May 2018 | pmid = 29775595 | doi = 10.1016/j.cell.2018.03.037 | pmc = 5967263 }}</ref><ref>{{Cite web |title=Osanetant - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/medicine-and-dentistry/osanetant |access-date=2022-11-24 |website=www.sciencedirect.com}}</ref> Another potential application for osanetant is in the treatment of ], as it has been found to block the effects of ] in animal models.<ref>{{cite journal |display-authors=6 |vauthors=De Souza Silva MA, Mello EL, Müller CP, Jocham G, Maior RS, Huston JP, Tomaz C, Barros M |date=May 2006 |title=The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys |journal=European Journal of Pharmacology |volume=536 |issue=3 |pages=269–278 |doi=10.1016/j.ejphar.2006.03.010 |pmid=16603151}}</ref><ref>{{cite journal |vauthors=Jocham G, Lezoch K, Müller CP, Kart-Teke E, Huston JP, de Souza Silva MA |date=September 2006 |title=Neurokinin receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core |journal=The European Journal of Neuroscience |volume=24 |issue=6 |pages=1721–1732 |doi=10.1111/j.1460-9568.2006.05041.x |pmid=17004936 |s2cid=29488484}}</ref> |
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Osanetant is being investigated by Acer Therapeutics as a treatment for severe vasomotor symptoms such as a hot flashes and flushes among people experiencing menopause.<ref>{{Cite journal |last=Acer Therapeutics Inc. |date=2022-09-13 |title=A Phase 2A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy, Safety and Pharmacokinetics (PK) of ACER-801 for Treatment of Moderate to Severe Vasomotor Symptoms (VMS) Associated With Menopause |url=https://clinicaltrials.gov/ct2/show/NCT05325775}}</ref> |
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==Synthesis== |
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Several different syntheses have been reported. Below are representative examples. |
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The reaction between 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile<ref>{{cite web | title = 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile | url = https://pubchem.ncbi.nlm.nih.gov/compound/15381168 | id = CID:22376623 | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> ('''1''') and ] ('''2''') gives 4-Cyano-4-(3,4-dichlorophenyl)-7-(oxan-2-yloxy)heptanoic aci <ref>{{cite web | title = 4-Cyano-4-(3,4-dichlorophenyl)-7-(oxan-2-yloxy)heptanoic acid | url = https://pubchem.ncbi.nlm.nih.gov/compound/15381168 | id = CID:15381168 | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> ('''3'''). Treatment with acid gives 3-propyl acetate, ('''4'''). Reduction of the imide with ] afforded ('''5'''). The reaction of this intermediate with benzoyl chloride gives ('''6'''). Treatment with mesyl chloride completed the synthesis of ('''7'''). |
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The reaction of 1-Benzyl-4-phenyl-4-piperidinol ('''1''') with ] and subsequent ] gave N-(1-Benzyl-4-phenylpiperidin-4-yl)formamide, ('''2'''). The reduction of the formamide with lithium aluminium hydride gave 1-benzyl-N-methyl-4-phenylpiperidin-4-amine ('''3'''). Reaction with acetic anhydride gave ('''4'''). Catalytic hydrogenation removal of the benzyl protecting group gave N-Methyl-N-(4-phenylpiperidin-4-yl)acetamide ('''5'''). |
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] completes the synthesis of Osanetant. |
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==CID:11119744== |
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Subsequent studies have shown that the Osanetant precursor is already a powerful BAT (biogenic amine transporter) substrate without the need for having to surmount the total synthesis of Osanetant. The Ki numbers in the patent for Ex 58 are NET = 2.4nM & DAT = 13.8nM. |
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This is not the first time that Sanofi produced a 3-arylpiperidine having BAT dopaminergic properties. For example, 3-piperidine |
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was reported in a previous patent.<ref>Lucien Nedelec, Jacques Guillaume, & Claude Dumont, {{US patent|4259337}} (1981 to Sanofi Aventis France).</ref> It was stated in the patent that such compounds can be expected to be able to treat depression, obesity, and Parkinson's disease. |
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{{clear}} |
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==References== |
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==References== |
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{{Reflist}} |
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<references/> |
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{{Neuropeptide agonists and antagonists}} |
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{{Neurokinin receptor modulators}} |
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{{pharma-stub}} |
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