BMS-641988: Difference between revisions

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{{Short description|Experimental drug for prostate cancer}}
{{Drugbox
{{Drugbox
| Verifiedfields =
| verifiedfields = changed
| Watchedfields =  
| verifiedrevid = 477002123
| verifiedrevid =  
| IUPAC_name = (2S)-N-[(1R)-1-Cyano-2-phenylethyl]-3-(4-cyanophenyl)-2-[[4-(trifluoromethyl)phenyl]methylamino]propanamide
| IUPAC_name = ''N''-[(3aR,4R,5R,7R,7aS)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-octahydro-1H-4,7-epoxyisoindol-5-yl]ethanesulfonamide
| image = BMS-641988_structure.png
| image = BMS-641988.svg
| width = 250
| width = 250px
| CAS_number = 1001350-96-4
 
| PubChem = 16054624
<!--Clinical data-->
| ChemSpiderID = 17286447
| tradename =  
| UNII = 9X0X8R0X0Q
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| KEGG = D09992
| pregnancy_US = <!-- A / B / C / D / X -->
| ChEMBL = 2103874
| pregnancy_category =  
| C=28
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| H=24
| legal_CA =  
| F=3
| legal_UK =  
| N=3
| legal_US =  
| O=1
| legal_status =  
| smiles = C1=CC=C(C=C1)C(C#N)C(C(=O)NC(C2=CC=C(C=C2)C#N)CNC3=CC=C(C=C3)C(F)(F)F)N
| routes_of_administration = [[Oral administration|By mouth]]
}}
| class = [[Nonsteroidal antiandrogen]]
 
<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound =  
| metabolism =  
| elimination_half-life =  
| excretion =


<!-- Identifiers -->
'''BMS-641988''' is an investigational drug developed by [[Bristol-Myers Squibb]] for the treatment of [[prostate cancer]]. It is a nonsteroidal antiandrogen that acts as an antagonist of the [[androgen receptor]].
| CAS_number_Ref =
| CAS_number = 1093276-09-5
| CAS_supplemental = <br />573738-99-5
| ATC_prefix =
| ATC_suffix =
| ATC_supplemental =
| PubChem = 24768935
| IUPHAR_ligand =
| DrugBank_Ref =
| DrugBank =
| ChemSpiderID_Ref =
| ChemSpiderID =
| UNII = W17M53Y8IM
| KEGG =
| ChEBI = 95017
| ChEMBL = 3932464
| synonyms =


<!--Chemical data-->
==Mechanism of Action==
| C=20 | H=20 | F=3 | N=3 | O=5 | S=1
BMS-641988 functions by inhibiting the activity of the [[androgen receptor]], a critical driver of prostate cancer cell growth. By blocking this receptor, BMS-641988 prevents the binding of androgens, such as [[testosterone]] and [[dihydrotestosterone]], which are necessary for the proliferation of prostate cancer cells.
| molecular_weight = 471.451 g/mol
| SMILES = CCS(=O)(=O)N[C@@H]1C[C@@]2([C@@H]3[C@H]([C@]1(O2)C)C(=O)N(C3=O)C4=CC(=C(C=C4)C#N)C(F)(F)F)C
| StdInChI_Ref =
| StdInChI = 1S/C20H20F3N3O5S/c1-4-32(29,30)25-13-8-18(2)14-15(19(13,3)31-18)17(28)26(16(14)27)11-6-5-10(9-24)12(7-11)20(21,22)23/h5-7,13-15,25H,4,8H2,1-3H3/t13-,14-,15+,18-,19+/m1/s1
| StdInChIKey_Ref =
| StdInChIKey = HYNANJUKEMCYEQ-HIGHGGLBSA-N
}}


'''BMS-641988''' is a [[nonsteroidal antiandrogen]] which was developed by [[Bristol-Myers Squibb]] for the treatment of [[prostate cancer]] but was never marketed.<ref name="AdisInsight">https://adisinsight.springer.com/drugs/800026026</ref><ref name="pmid19654297">{{cite journal | vauthors = Attar RM, Jure-Kunkel M, Balog A, Cvijic ME, Dell-John J, Rizzo CA, Schweizer L, Spires TE, Platero JS, Obermeier M, Shan W, Salvati ME, Foster WR, Dinchuk J, Chen SJ, Vite G, Kramer R, Gottardis MM | title = Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer | journal = Cancer Res. | volume = 69 | issue = 16 | pages = 6522–30 | date = August 2009 | pmid = 19654297 | doi = 10.1158/0008-5472.CAN-09-1111 | url = }}</ref><ref name="pmid26861003">{{cite journal | vauthors = Cabeza M, Sánchez-Márquez A, Garrido M, Silva A, Bratoeff E | title = Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases | journal = Curr. Med. Chem. | volume = 23 | issue = 8 | pages = 792–815 | date = 2016 | pmid = 26861003 | pmc = 5412001 | doi = 10.2174/0929867323666160210125642| url = http://www.ingentaconnect.com/contentone/ben/cmc/2016/00000023/00000008/art00005?crawler=true&mimetype=application/pdf}}</ref> It acts as a [[potency (pharmacology)|potent]] [[competitive antagonist]] of the [[androgen receptor]] (AR) (K<sub>i</sub> = 10&nbsp;nM; {{abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}} = 56&nbsp;nM).<ref name="pmid26861003" /> The drug was found to have 20-fold higher [[affinity (pharmacology)|affinity]] for the AR than [[bicalutamide]] in [[MDA-MB-453]] [[cell (biology)|cell]]s, and showed 3- to 7-fold the [[antiandrogen]]ic activity of bicalutamide ''[[in vitro]]''.<ref name="pmid21426013">{{cite journal | vauthors = Vasaitis TS, Njar VC | title = Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments | journal = Future Med Chem | volume = 2 | issue = 4 | pages = 667–80 | date = April 2010 | pmid = 21426013 | doi = 10.4155/fmc.10.14 | url = }}</ref> It may have some weak [[partial agonist]] activity at the androgen receptor.<ref name="pmid21426013" /> BMS-641988 is [[biotransformation|transformed]] by [[CYP3A4]] into [[BMS-570511]], and this [[metabolite]] is then [[redox|reduced]] to [[BMS-501949]] by [[cytosol]]ic [[reductase]]s.<ref name="pmid21131556">{{cite journal | vauthors = Rathkopf D, Liu G, Carducci MA, Eisenberger MA, Anand A, Morris MJ, Slovin SF, Sasaki Y, Takahashi S, Ozono S, Fung NK, Cheng S, Gan J, Gottardis M, Obermeier MT, Reddy J, Zhang S, Vakkalagadda BJ, Alland L, Wilding G, Scher HI | title = Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer | journal = Clin. Cancer Res. | volume = 17 | issue = 4 | pages = 880–7 | date = February 2011 | pmid = 21131556 | pmc = 3070382 | doi = 10.1158/1078-0432.CCR-10-2955 | url = }}</ref><ref name="pmid21426013" /> All three compounds show similar [[antiandrogen]]ic activity.<ref name="pmid21131556" /> In addition to its antiandrogenic activity, BMS-641988 shows activity as a [[negative allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]], and can produce [[seizure]]s in animals at sufficiently high doses.<ref name="BarrishCarter2010">{{cite book|author1=Joel Barrish|author2=Percy Carter|author3=Peter Cheng|author4=Robert Zahler|title=Accounts in Drug Discovery: Case Studies in Medicinal Chemistry|url=https://books.google.com/books?id=jHIoDwAAQBAJ&pg=PA120|date=30 September 2010|publisher=Royal Society of Chemistry|isbn=978-1-84973-198-0|pages=120–}}</ref> It also shows some [[drug-induced QT prolongation]].<ref name="BarrishCarter2010" /> BMS-641988 reached [[Phases of clinical research#Phase I|phase I]] [[clinical trial]]s prior to the discontinuation of its development.<ref name="AdisInsight" /> The clinical development of BMS-641988 was terminated due to the occurrence of a seizure in a patient during a phase I study.<ref name="pmid21131556" />
==Development and Clinical Trials==
BMS-641988 was developed as part of a series of compounds aimed at improving the treatment of [[castration-resistant prostate cancer]] (CRPC). Preclinical studies demonstrated its potential efficacy in inhibiting tumor growth. However, during clinical trials, concerns about its safety profile, particularly regarding [[seizure]] risk, led to the discontinuation of its development.


==References==
==Pharmacokinetics==
{{Reflist}}
The pharmacokinetic profile of BMS-641988 includes its absorption, distribution, metabolism, and excretion characteristics. It was designed to have a favorable oral bioavailability and a half-life suitable for once-daily dosing. The drug undergoes hepatic metabolism, primarily via the [[cytochrome P450]] enzyme system.


==External links==
==Safety and Efficacy==
* [https://adisinsight.springer.com/drugs/800026026 BMS-641988 - AdisInsight]
While BMS-641988 showed promise in preclinical models, its clinical development was halted due to adverse effects observed in early-phase trials. The primary concern was the occurrence of seizures, which posed significant safety risks to patients.


==Related Pages==
* [[Prostate cancer]]
* [[Androgen receptor]]
* [[Nonsteroidal antiandrogen]]
* [[Castration-resistant prostate cancer]]
* [[Bristol-Myers Squibb]]


{{Androgen receptor modulators}}
[[Category:Experimental cancer drugs]]
 
[[Category:Abandoned drugs]]
[[Category:GABAA receptor negative allosteric modulators]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Nitriles]]
[[Category:Nonsteroidal antiandrogens]]
[[Category:Nonsteroidal antiandrogens]]
[[Category:Prostate cancer]]
[[Category:Prostate cancer]]
[[Category:Sulfonamides]]
[[Category:Trifluoromethyl compounds]]
[[Category:Imides]]
{{Genito-urinary-drug-stub}}
{{Antineoplastic-drug-stub}}
{{dictionary-stub1}}
<gallery>
File:BMS-641988.svg|BMS-641988
</gallery>

Latest revision as of 19:08, 22 March 2025

Experimental drug for prostate cancer


{{Drugbox | verifiedfields = changed | verifiedrevid = 477002123 | IUPAC_name = (2S)-N-[(1R)-1-Cyano-2-phenylethyl]-3-(4-cyanophenyl)-2-[[4-(trifluoromethyl)phenyl]methylamino]propanamide | image = BMS-641988_structure.png | width = 250 | CAS_number = 1001350-96-4 | PubChem = 16054624 | ChemSpiderID = 17286447 | UNII = 9X0X8R0X0Q | KEGG = D09992 | ChEMBL = 2103874 | C=28 | H=24 | F=3 | N=3 | O=1 | smiles = C1=CC=C(C=C1)C(C#N)C(C(=O)NC(C2=CC=C(C=C2)C#N)CNC3=CC=C(C=C3)C(F)(F)F)N }}

BMS-641988 is an investigational drug developed by Bristol-Myers Squibb for the treatment of prostate cancer. It is a nonsteroidal antiandrogen that acts as an antagonist of the androgen receptor.

Mechanism of Action[edit]

BMS-641988 functions by inhibiting the activity of the androgen receptor, a critical driver of prostate cancer cell growth. By blocking this receptor, BMS-641988 prevents the binding of androgens, such as testosterone and dihydrotestosterone, which are necessary for the proliferation of prostate cancer cells.

Development and Clinical Trials[edit]

BMS-641988 was developed as part of a series of compounds aimed at improving the treatment of castration-resistant prostate cancer (CRPC). Preclinical studies demonstrated its potential efficacy in inhibiting tumor growth. However, during clinical trials, concerns about its safety profile, particularly regarding seizure risk, led to the discontinuation of its development.

Pharmacokinetics[edit]

The pharmacokinetic profile of BMS-641988 includes its absorption, distribution, metabolism, and excretion characteristics. It was designed to have a favorable oral bioavailability and a half-life suitable for once-daily dosing. The drug undergoes hepatic metabolism, primarily via the cytochrome P450 enzyme system.

Safety and Efficacy[edit]

While BMS-641988 showed promise in preclinical models, its clinical development was halted due to adverse effects observed in early-phase trials. The primary concern was the occurrence of seizures, which posed significant safety risks to patients.

Related Pages[edit]

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