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Updating {{drugbox}} (changes to verified fields - updated 'ChemSpiderID_Ref', 'DrugBank_Ref', 'ChEMBL_Ref', 'ChEBI_Ref', 'StdInChI_Ref', 'StdInChIKey_Ref', 'ChEBI_Ref') per [[Wikipedia:WikiProject Chemicals/Chembox validation|Chem/Drugbox validation
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{{Short description|Chemical compound}}
{{drugbox
{{Infobox drug
| Verifiedfields = changed
| Verifiedfields = changed
| UNII_Ref = {{fdacite|changed|FDA}}
| Watchedfields = changed
| verifiedrevid = 443328897
| UNII = 3YN0602W4W
| IUPAC_name = (2''S'')-2-Hydroxy-3-methyl-''N''-((1''S'')-1-methyl-2-{[(1''S'')-3-methyl-2-oxo-2,3,4,5-tetrahydro-1''H''-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide
| verifiedrevid = 408751858
| image = Semagacestat.svg
| IUPAC_name = (2''S'')-2-hydroxy-3-methyl-''N''-((1''S'')-1-methyl-2-{[(1''S'')-3-methyl-2-oxo-2,3,4,5-tetrahydro-1''H''-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide

| image = Semagacestat structure.svg
<!--Clinical data-->
| synonyms = LY-450139
| tradename =
| CAS_number = 425386-60-3
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| CAS_supplemental =
| ATC_prefix = none
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| ATC_suffix =
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| ATC_supplemental =
| PubChem = 9843750
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Development terminated
| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism = [[CYP3A4]], [[CYP3A5|3A5]]<ref name="pmid20075192" />
| elimination_half-life = 2.4 hours in circulation
| excretion = 87% [[renal]] (44% unchanged, 43% as metabolites)

<!--Identifiers-->
| IUPHAR_ligand = 6978
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 425386-60-3
| ATC_prefix = None
| ATC_suffix =
| ATC_supplemental =
| PubChem = 9843750
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| DrugBank =
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 520733
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3YN0602W4W
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D09377
| KEGG = D09377
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| chemical_formula =
| ChemSpiderID = 8019465
| C=19 | H=27 | N=3 | O=4

| molecular_weight = 361.434 g/mol
<!--Chemical data-->
| smiles = c12ccccc2CCN(C)C(=O)C1NC(=O)C(C)NC(=O)C(O)C(C)C
| chemical_formula =
| bioavailability =
| protein_bound =
| C=19 | H=27 | N=3 | O=4
| smiles = C[C@@H](C(=O)N[C@H]1C2=CC=CC=C2CCN(C1=O)C)NC(=O)[C@H](C(C)C)O
| metabolism = [[CYP3A4]], [[CYP3A5|3A5]]<ref name="PMID20075192" />
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| elimination_half-life = 2.4 hours in circulation
| StdInChI = 1S/C19H27N3O4/c1-11(2)16(23)18(25)20-12(3)17(24)21-15-14-8-6-5-7-13(14)9-10-22(4)19(15)26/h5-8,11-12,15-16,23H,9-10H2,1-4H3,(H,20,25)(H,21,24)/t12-,15-,16-/m0/s1
| excretion = 87% [[renal]] (44% unchanged, 43% as metabolites)
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| StdInChIKey = PKXWXXPNHIWQHW-RCBQFDQVSA-N
| pregnancy_US = <!-- A / B / C / D / X -->
| synonyms = LY-450139
| pregnancy_category= N/A
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Investigational
| routes_of_administration = Oral
}}
}}


'''Semagacestat''' ('''LY450139''') was a candidate drug for a causal therapy against [[Alzheimer's disease]]. It was originally developed by [[Eli Lilly and Company|Eli Lilly]] and [[Élan]], and [[clinical trial]]s were conducted by Eli Lilly. Phase III trials included over 3000 patients,<ref name="Spreitzer" /><ref name="Prous" /> but in August 2010, a disappointing interim analysis, in which semagacestat performed less well than the placebo, led to investigators being instructed to tell subjects to stop taking the drug.
'''Semagacestat''' ('''LY-450139''') was a candidate drug for a causal therapy against [[Alzheimer's disease]]. It was originally developed by [[Eli Lilly and Company|Eli Lilly]] and [[Élan|Elan]], and [[clinical trial]]s were conducted by Eli Lilly. Phase III trials included over 3000 patients,<ref name="Spreitzer" /><ref name="Prous" /> but in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped.


== Mechanism of action ==
== Mechanism of action ==
[[Beta amyloid|β-amyloid]] is a peptide of 39 to 43 amino acids. The isoforms with 40 and 42 amino acids (Aβ40/42) are the main constituents of [[amyloid plaque]]s in the brains of Alzheimer's disease patients. β-amyloid is formed by [[proteolysis]] of [[Amyloid precursor protein|APP]]. Research on laboratory rats suggest that the soluble form of this peptide is a causative agent in the development of Alzheimer's.
[[Beta amyloid|β-Amyloid]] is a peptide of 39 to 43 amino acids. The isoforms with 40 and 42 amino acids (Aβ40/42) are the main constituents of [[amyloid plaque]]s in the brains of Alzheimer's disease patients. β-Amyloid is formed by [[proteolysis]] of [[amyloid precursor protein]] (APP). Research on laboratory rats suggest that the soluble form of this peptide is a causative agent in the development of Alzheimer's.


Semagacestat blocks the enzyme [[Gamma secretase|γ-secretase]], which (along with [[Beta secretase|β-secretase]]) is responsible for APP proteolysis.<ref name="Prous" />
Semagacestat blocks the enzyme [[Gamma secretase|γ-secretase]], which (along with [[Beta secretase|β-secretase]]) is responsible for APP proteolysis.<ref name="Prous" />
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A number of issues have already been raised during clinical trials:
A number of issues have already been raised during clinical trials:
* Phase I and II studies showed a decrease of Aβ40/42 concentration in the [[blood plasma]] about three hours after application of semagacestat, but an increase of 300% 15 hours after application. No reduction was shown in the [[cerebrospinal fluid]]. As a consequence, the phase III studies worked with much higher doses.<ref name="Zsilavecz" />
* Phase I and II studies showed a decrease of Aβ40/42 concentration in the [[blood plasma]] about three hours after application of semagacestat, but an increase of 300% 15 hours after application. No reduction was shown in the [[cerebrospinal fluid]]. As a consequence, the phase III studies worked with much higher doses.<ref name="Zsilavecz" />
* γ-secretase has other targets, for example the [[notch receptor]]. It is not known whether this could cause long-term side effects.<ref name="Zsilavecz" />
* γ-Secretase has other targets, for example the [[notch receptor]]. It is not known whether this could cause long-term side effects.<ref name="Zsilavecz" />
* In a 2008, histological analysis of post-mortem brains from deceased subjects who had previously been enrolled in a phase 1 study of an experimental vaccine (Elan AN1792) demonstrated that the drug appeared to have cleared patients of amyloid plaques but did not have any significant effect on their dementia, which in some people's mind, cast doubt on the utility of approaches lowering β-amyloid levels.<ref name="Holmes" />
* In a 2008, histological analysis of post-mortem brains from deceased subjects who had previously been enrolled in a phase 1 study of an experimental vaccine (Elan AN1792) demonstrated that the drug appeared to have cleared patients of amyloid plaques but did not have any significant effect on their dementia, which in some people's mind cast doubt on the utility of approaches lowering β-amyloid levels.<ref name="Holmes" />
* A notable feature of the results of the semagacestat phase III interim analysis is that subjects on treatment did significantly worse in cognitive assessment and activities of daily living than did subjects in the placebo group. This contrasts with the results from the phase III trial of Myriad's γ-secretase modulator [[tarenflurbil]], which found that the subjects in the treatment group tracked the placebo control group very closely. The implications of this finding on other companies undertaking development of molecules targeting γ-secretase is not yet clear.
* A notable feature of the results of the semagacestat phase III interim analysis is that subjects on treatment did significantly worse in cognitive assessment and activities of daily living than did subjects in the placebo group. This contrasts with the results from the phase III trial of Myriad's γ-secretase modulator [[tarenflurbil]], which found that the subjects in the treatment group tracked the placebo control group very closely. The implications of this finding on other companies undertaking development of molecules targeting γ-secretase is not clear.


== References ==
== References ==
{{Reflist|2|refs=
{{Reflist|2|refs=

<ref name="PMID20075192">{{cite journal|pmid=20075192|year=2010|last1=Yi|first1=P|last2=Hadden|first2=C|last3=Kulanthaivel|first3=P|last4=Calvert|first4=N|last5=Annes|first5=W|last6=Brown|first6=T|last7=Barbuch|first7=RJ|last8=Chaudhary|first8=A|last9=Ayan-Oshodi|first9=MA|title=Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans|volume=38|issue=4|pages=554–65|doi=10.1124/dmd.109.030841|journal=Drug metabolism and disposition: the biological fate of chemicals}}</ref>
<ref name="pmid20075192">{{cite journal | vauthors = Yi P, Hadden C, Kulanthaivel P, Calvert N, Annes W, Brown T, Barbuch RJ, Chaudhary A, Ayan-Oshodi MA, Ring BJ | display-authors = 6 | title = Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans | journal = Drug Metabolism and Disposition | volume = 38 | issue = 4 | pages = 554–65 | date = April 2010 | pmid = 20075192 | doi = 10.1124/dmd.109.030841 | s2cid = 19707025 }}</ref>
<ref name="Spreitzer">{{cite journal

| author = H. Spreitzer
<ref name="Spreitzer">{{cite journal | vauthors = Spreitzer H | date = July 21, 2008 | title = Neue Wirkstoffe – Semagacestat | journal = Österreichische Apothekerzeitung | issue = 15/2008 | pages = 780 | language = German }}</ref>
| date = July 21, 2008

| title = Neue Wirkstoffe – Semagacestat
| journal = Österreichische Apothekerzeitung
| issue = 15/2008
| pages = 780
| language = German
}}</ref>
<ref name="Prous">[http://www.prous.com/molecules/default.asp?ID=174 Prous Science: Molecule of the Month July 2008]</ref>
<ref name="Prous">[http://www.prous.com/molecules/default.asp?ID=174 Prous Science: Molecule of the Month July 2008]</ref>

<ref name="identity">{{ClinicalTrialsGov|NCT00594568|Effect of LY450139 on the Long Term Progression of Alzheimer's Disease}}</ref>
<ref name="identity">{{ClinicalTrialsGov|NCT00594568|Effect of LY450139 on the Long Term Progression of Alzheimer's Disease}}</ref>

<ref name="identity2">{{ClinicalTrialsGov|NCT00762411|Effects of LY450139, on the Progression of Alzheimer's Disease as Compared With Placebo (IDENTITY-2)}}</ref>
<ref name="identity2">{{ClinicalTrialsGov|NCT00762411|Effects of LY450139, on the Progression of Alzheimer's Disease as Compared With Placebo (IDENTITY-2)}}</ref>

<ref name="identityXT">{{ClinicalTrialsGov|NCT00762411|A Study in Semagacestat for Alzheimer's Patients (Identity XT)}}</ref>
<ref name="identityXT">{{ClinicalTrialsGov|NCT00762411|A Study in Semagacestat for Alzheimer's Patients (Identity XT)}}</ref>

<ref name="Holmes">
<ref name="Holmes">{{cite journal | vauthors = Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA | display-authors = 6 | title = Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial | journal = Lancet | volume = 372 | issue = 9634 | pages = 216–23 | date = July 2008 | pmid = 18640458 | doi = 10.1016/S0140-6736(08)61075-2 | s2cid = 18340153 }}</ref>
{{cite journal

|author=Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JAR
<ref name="Zsilavecz">{{cite journal | vauthors = Schubert-Zsilavecz M, Wurglics M | title = Semagacestat | journal = Neue Arzneimittel | date = 2008–2009 }}</ref>
|title=Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial

|journal=The Lancet
<ref name="PT20100818">{{cite web | title = Lilly hit by spectacular failure of Phase III Alzheimer's candidate | url =http://www.pharmatimes.com/news/lilly_hit_by_spectacular_failure_of_phase_iii_alzheimers_candidate_982579 | work = PharmaTimes | date = 18 August 2010 }}</ref>
|volume=372

|issue=9634
|pages=216–233
|year=2008
|month=July
|doi=10.1016/S0140-6736(08)61075-2
|url=
|accessdate=2008-07-17
|format=Subscription required
|pmid=18640458
}}</ref>
<ref name="Zsilavecz">Schubert-Zsilavecz, M, Wurglics, M, ''Neue Arzneimittel 2008/2009''</ref>
<ref name="PT20100818">[http://www.pharmatimes.com/WorldNews/article.aspx?id=18386&src=EWorldNews PharmaTimes 18 August 2010]</ref>
}}
}}


{{Anti-dementia drugs}}
{{Anti-dementia drugs}}


[[Category:Abandoned drugs]]
[[Category:Secondary alcohols]]
[[Category:Alzheimer's disease]]
[[Category:Antidementia agents]]
[[Category:Antidementia agents]]
[[Category:Alzheimer's disease]]
[[Category:Benzazepanes]]
[[Category:Eli Lilly and Company]]
[[Category:Carboxamides]]
[[Category:Benzazepines]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:Lactams]]
[[Category:Lactams]]
[[Category:Amides]]
[[Category:Gamma secretase inhibitors]]
[[Category:Alcohols]]

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[[sr:Semagacestat]]
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