Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Balog, Aaron; Rampulla, Richard; Martin, Grégory; Krystek, Stanley R.; Attar, Ricardo M.; Dell-John, Janet; DiMarco, John; Fairfax, David J.; Gougoutas, Jack Z.; Holst, Christian L.; Nation, Andrew; Rizzo, Christopher; Rossiter, Lana M.; Schweizer, Liang; Shan, Weifang; Spergel, Steven H.; Spires, Thomas E.; Cornelius, Georgia; Gottardis, Marco M.; Trainor, George L.; Vite, Gregory D.; Salvati, Mark

doi:10.1021/acsmedchemlett.5b00173

Cited by 18 publications

(11 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Curtius rearrangement of 77 provided amine 78 in good yields. A series of amides, sulfamides, carbamates, ureas, and sulfonamides were prepared from amine 78 , leading to the discovery of lead compound 73 (Scheme ) . Compound 73 was tested in the human prostate cancer xenograft model CWR22‐BMSLD1 demonstrating superior efficacy compared to bicalutamide and robust pharmacokinetic and pharmacodynamic profiles.…”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

View full text Add to dashboard Cite

The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

show abstract

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

View full text Add to dashboard Cite

show abstract

“…Surprisingly, ( S )-BMS alone caused substantial hyperspeckling, comparable to that of R1881. To explore the significance of this result, which appeared to contradict literature inferences ( 7 , 10 ), we prepared a series “EITM-17##” of cognate derivatives ( Fig. 1 B ).…”

Section: Resultsmentioning

confidence: 91%

“…Establishing a predictive AR model for antagonists is hampered by the lack of structural information about AR bound to antagonist in open conformation. The AR antagonist BMS-641988 ( 6 – 8 ) has a chiral center at C-5 and an endo substituent [( R )-BMS]. Its unknown ( S )-enantiomer [( S )-BMS] was postulated to also be an antagonist ( 7 ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Paradoxical androgen receptor regulation by small molecule enantiomers

Patsch

Liu

Zapotoczny

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Small molecules that target the androgen receptor (AR) are the mainstay of therapy for lethal castration-resistant prostate cancer (CRPC), yet existing drugs lose their efficacy during continued treatment. This evolution of resistance is due to heterogenous mechanisms which include AR mutations causing the identical drug to activate instead of inhibit the receptor. Understanding in molecular detail the paradoxical phenomenon wherein an AR antagonist is transformed into an agonist by structural mutations in the target receptor is thus of paramount importance. Herein, we describe a reciprocal paradox: opposing antagonist and agonist AR regulation determined uniquely by enantiomeric forms of the same drug structure. The antiandrogen BMS-641988, which has (R)-chirality at C-5 encompasses a previously uncharacterized (S)-stereoisomer that is, surprisingly, a potent agonist of AR, as demonstrated by transcriptional assays supported by cell imaging studies. This duality was reproduced in a series of novel compounds derived from the BMS-641988 scaffold. Coupled with in silico modeling studies, the results inform an AR model that explains the switch from potent antagonist to high-affinity agonist in terms of C-5 substituent steric interactions with helix 12 of the ligand binding site. They imply strategies to overcome AR drug resistance and demonstrate that insufficient enantiopurity in this class of AR antagonist can confound efforts to correlate structure with function.

show abstract

“…In this regard, Kandil et al [128] synthesised umbelliferone derivatives merging two independent in silico pharmacophores based on virtual screening in vivo, it was selected for clinical development and the outcomes of two Phase I studies in patients with CRPC (NCT00644488 and NCT00326586) have been published [130] .…”

Section: Seviteronel (5mentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

View full text Add to dashboard Cite

Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

show abstract

Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Cited by 18 publications

References 16 publications

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Paradoxical androgen receptor regulation by small molecule enantiomers

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Contact Info

Product

Resources

About