JP2021535923A - エストロゲン受容体を標的にするアンタゴニスト - Google Patents
エストロゲン受容体を標的にするアンタゴニスト Download PDFInfo
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- JP2021535923A JP2021535923A JP2021514339A JP2021514339A JP2021535923A JP 2021535923 A JP2021535923 A JP 2021535923A JP 2021514339 A JP2021514339 A JP 2021514339A JP 2021514339 A JP2021514339 A JP 2021514339A JP 2021535923 A JP2021535923 A JP 2021535923A
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Abstract
Description
本国際出願は、2018年9月18日に出願された米国特許仮出願第62/730,464号の利益を主張し、その全体が参照により本明細書に援用されている。
本発明は、国立マイノリティ健康格差研究所(NIMHD)により拠出された2G12MD007595の下の政府支援で行った。政府は、本発明に特定の権利を有する。
本開示は、エストロゲン受容体に競合して結合して受容体をアンタゴナイズする、下方制御する、もしくは受容体に共有結合する、またはこれらの作用機序の組合せにより作用し、エストロゲンシグナル伝達経路を遮断し、ER依存性乳癌を阻害する化合物に関する。本開示は、これらのERを標的にする化合物を含む医薬組成物、及び、がんを含む、エストロゲン受容体が媒介する病理学的進行を治療するための、当該医薬組成物の使用方法にもまた関する。
乳癌は、世界中で女性の最も一般的ながんとして残っており、2012年には170万人の新規症例があった(全体にて2番目に一般的ながんであった)。このことは、新規の全てのがんの症例の約12%、そして、女性の全てのがんの25%を表している。乳癌のおよそ80%はエストロゲン受容体陽性(ER+)であり[1、2]、これらの患者の大部分にとって、内分泌腺治療法は、アジュバント及び高度設定の両方における、適切なオプションである。ER+乳癌に対する現在の内分泌腺治療法は、最適のアウトカムに対する様々な帰結に使用可能な3つのレジメンオプション:SERM(例えばタモキシフェン、ラロキシフェン、トレミフェン)、アロマターゼ阻害剤(アナストロゾール、エクセメスタン、レトロゾールを含むAI)、及びSERD(フルベストラント)を含む[3]。タモキシフェンは、閉経前患者、及び、DCIS診断後に二次的な化学的予防を必要とする女性に対する第一線の剤である。閉経後女性において、進行するのにより好ましい時間、及び深刻度の低い副作用が理由で、タモキシフェンよりもAIが一般的に好ましい[4、5]。しかし、進行した転移性の乳癌を有する大部分の患者は、再発性及び/または進行性疾患において、ERαの発現を維持しながらも、タモキシフェンまたはAI治療に対する耐性が最終的に発達する。この臨床情報は、以前の内分泌腺剤に対して交差耐性でない、効果的なERを標的にするアンタゴニストを用いるための、実現可能な治療の論理的証拠を提供する。
[式中、R1置換基の結合点は、R1の置換基であるホウ素原子上に存在する。]。式(I)の化合物の例は化合物1であり、式(I)の化合物1を合成するための例示的なスキームを図1に示す。
[式中、R1置換基の結合点は、R1の置換基であるホウ素原子上に存在する。]。式(II)の化合物の例は化合物2であり、式(II)の化合物2を合成するための例示的なスキームを図2に示す。
[式中、R1置換基の結合点は、R1の置換基であるホウ素原子上に存在する。]。式(III)の化合物の例は化合物3〜8、15、16であり、式(III)の化合物3〜8、15、16を合成するための例示的なスキームは例えば、図3、図4、図5、図6、図7、図8、及び図15に示す。
[式中、R1置換基の結合点は、R1の置換基であるホウ素原子上に存在する。]。式(IV)の化合物の例は化合物9〜12であり、式(IV)の化合物9〜12を合成するための例示的なスキームは、図9、10、11、及び12に示す。
[式中、R1置換基の結合点は、R1の置換基であるホウ素原子上に存在する。]。式(V)の化合物の例は化合物13であり、式(V)の化合物13を合成するための例示的なスキームは図13に示す。
[式中、R1置換基の結合点は、以下に示す実施例化合物構造によってさらに完全に示されるように、R1の置換基であるホウ素原子上に存在する。]。式(VI)の化合物の例は化合物14であり、式(VI)の化合物14を合成するための例示的なスキームは図14に示す。
開示した、ERを標的にするアンタゴニストの、エストロゲン受容体への結合親和性を評価するために、試験化合物がフルオモンリガンドと競合するLanthaScreen TR−FRETアッセイ(Life Technologies)を使用し、置換割合は、置換されたトレーサーからの蛍光強度に定量的に相関した。図16は、それぞれ、2.40nM及び3.07nMにて測定したIC50値を有する、化合物1(式Iの実施例)及び化合物4(式IIIの実施例)の、競合結合曲線を示す。
化合物1のER拮抗は不可逆性である。
化合物1は、乳癌細胞の増殖を阻害する。
化合物1は、マウスにおける異種移植片胸部腫瘍増殖を阻害する。
化合物4ではなく化合物1が、マウス子宮内でアゴニスト活性を示す。
化合物1の経口生物学的利用能及び代謝安定性を試験するために、5mg/kgの1回経口用量をSprague Dawleyラットに投与し、様々な時間間隔で血漿サンプルを収集し、化合物1の濃度を測定した。化合物1のPKプロファイルを図5にプロットする。AUC値が10,000ng.h.mL−1に達しながら、ピーク濃度は1200ng/mLを超えた。これは、優れた薬剤暴露プロファイルを示している。ZB499の経口生物学的利用能が強力に示されることは、最初に受ける代謝を最小限に抑え、吸収を向上させるという二重の能力を有するボロン酸部分に起因するものである。
エストロゲン受容体陽性(ER+)乳癌細胞株、抗エストロゲン薬治療に感受性のあるMCF7、及び、抗エストロゲン薬治療に耐性を有することになった、その派生物である細胞株において、我々は、化合物1及び化合物4のアンタゴニスト活性を試験した。細胞を、各種用量でそれぞれ、公知のSERM、4−ヒドロキシタモキシフェン、SERD、フルベストラント、化合物1、及び化合物4で処理し、細胞増殖を50%を害するのに必要な化合物の濃度として定義される、各治療のIC50値を得た。結果を表1に示す。
引用した参考文献:
1. Jasani B, Douglas−Jones A, Rhodes A, Wozniak S, Barrett−Lee PJ, Gee J, Nicholson R. Measurement of estrogen receptor status by immunocytochemistry in paraffin wax sections. Methods Mol Med. 2006;120:127−46.
2. Setiawan VW, Monroe KR, Wilkens LR, Kolonel LN, Pike MC, Henderson BE. Breast cancer risk factors defined by estrogen and progesterone receptor status: the multiethnic cohort study. Am J Epidemiol. 2009 May 15;169(10):1251−9.
3. Barrios C, Forbes JF, Jonat W, Conte P, Gradishar W, Buzdar A, Gelmon K, Gnant M, Bonneterre J, Toi M, Hudis C, Robertson JF. The sequential use of endocrine treatment for advanced breast cancer: where are we? Ann Oncol. 2012, 23(6):1378−86.
4. Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first−line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000;18: 3758− 3767.
5. Nabholtz JM, Bonneterre J, Buzdar A et al. Anastrozole (Arimidex) versus tamoxifen as first−line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003;39: 1684− 1689.
6. Hammond et al., Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer, Journal of Clinical Oncology, Vol 28, Issue 16, pp 2784−2795 (2010).
7. Wilson VS, Bobseine K, Gray LE Jr. Development and characterization of a cell line that stably expresses an estrogen−responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci. 2004, Sep;81(1):69−77.
Claims (18)
- 式(I)〜式(VI)のうちの1つに従った化合物、またはその塩、その溶媒和物、もしくはその塩の溶媒和物。
- 増殖性疾患の治療を必要とする哺乳類における、前記増殖性疾患の前記治療で使用するための、請求項1に記載の化合物。
- がんの治療を必要とする哺乳類における、前記がんの前記治療で使用するための、請求項1に記載の化合物。
- エストロゲン受容体の制御を必要とする哺乳類における、前記エストロゲン受容体の制御で使用するための、請求項1に記載の化合物。
- 薬剤として使用するための、請求項1〜4のいずれか1項に記載の化合物を含む組成物。
- 請求項1〜11のいずれか1項に記載の化合物、薬学的に許容される塩、溶媒和物、または組成物と、薬学的に許容される担体と、を含む医薬組成物。
- 経腸投与に好適な、請求項12に記載の医薬組成物。
- 前記医薬組成物が経口投与に好適な、請求項13に記載の医薬組成物。
- 非経口的投与に好適な、請求項12に記載の医薬組成物。
- 対象に、請求項1〜11のいずれか1項に記載の化合物、薬学的に許容される塩、溶媒和物、もしくは組成物、または、請求項12〜15のいずれか1項に記載の医薬組成物を投与することを含む、乳癌の治療方法。
- 前記乳癌がER陽性乳癌である、請求項16に記載の方法。
- 前記対象が変異ER−αタンパク質を発現する、請求項17に記載の方法。
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PCT/US2019/050573 WO2020055973A1 (en) | 2018-09-12 | 2019-09-11 | Estrogen receptor targeting antagonists |
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