JP2016532697A - リン酸塩輸送阻害のための化合物及び方法 - Google Patents
リン酸塩輸送阻害のための化合物及び方法 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)の下で、2013年8月9日出願の米国出願第61/864,215号、及び2014年2月6日出願の米国出願第61/936,715号の優先権を主張するものであり、これらはそれぞれ、参照によりその全体が本明細書に組み込まれる。
本出願に関連する配列表は、紙のコピーの代わりにテキスト形式で提供され、ここで参照により本明細書に組み込まれる。配列表を含むテキストファイルの名称は、「ARDE_017_01WO_ST25.txt」である。本テキストファイルは193KBであり、2014年8月8日に作成され、EFS−Webを介して電子的に提出されている。
(a)高リン血症、任意に食後高リン血症を治療するための方法、
(b)腎疾患、任意に慢性腎疾患(CKD)または末期腎疾患(ESRD)を治療するための方法、
(c)血清クレアチニンレベルを低減させるための方法、
(d)タンパク尿を治療するための方法、
(e)腎代替療法(RRT)、任意に透析までの時間を遅らせるための方法、
(f)FGF23レベルを低減させるための方法、
(g)活性型ビタミンDの高リン血症作用を低減させるための方法、
(h)副甲状腺機能亢進症、任意に続発性副甲状腺機能亢進症を軽減させるための方法、
(i)血清副甲状腺ホルモン(PTH)を低減させるための方法、
(j)任意に食後血清リンによって誘導される、内皮障害を改善するための方法、
(k)血管石灰化、任意に内膜局在性血管石灰化を低減させるための方法、
(l)尿中亜リン酸を低減させるための方法、
(m)血清リンレベルを正常化するための方法、
(n)高齢患者のリン負荷を低減させるための方法、
(o)食事性リン酸塩取り込みを減少させるための方法、
(p)腎肥大を低減させるための方法、及び
(q)心肥大を低減させるための方法、のうちの1つ以上から選択される方法をもたらす。
本発明の実施形態は、例えば、胃腸内腔の上皮膜の中またはそれに隣接するpHを調整すること、小腸内の水吸収を減少させること、またはその両方によって、胃腸管内のリン酸塩輸送/取り込みを阻害または低減することができる化合物に関する。pH調整化合物の例としては、小腸内の重炭酸塩分泌(すなわち、十二指腸の重炭酸塩分泌、すなわちDBS)を刺激するか、小腸内の酸/プロトン分泌を阻害するか、または両方を行うものが挙げられる。
ある特定の実施形態では、本化合物は、P2Y作動薬(またはP2Y受容体作動薬)である。P2Y受容体は、プリン作動性のGタンパク質結合受容体のファミリーを指す。ヒトP2Y受容体の例としては、P2Y1、P2Y2、P2Y4、P2Y5、P2Y6、P2Y8、P2Y9、P2Y10、P2Y11、P2Y12、P2Y13、及びP2Y14が挙げられる。P2Y受容体の主な天然または内因性リガンドは、アデノシン5’−三リン酸塩(ATP)、アデノシン5’−二リン酸塩(ADP)、ウリジン5’−三リン酸塩(UTP)、ウリジン5’−二リン酸塩(UDP)、及びUDP−グルコース(または他のUDP糖類)である。Ap4Uなどのジヌクレオチドも、自然発生のP2Y作動薬である。
ある特定の実施形態では、本化合物は、アデノシンA2b受容体作動薬、任意に選択的作動薬である。アデノシンは、A1、A2A、A2B、及びA3アデノシン受容体(AR)と名付けられた4つの受容体サブタイプにおける局在性調節因子として作用することによって、その生理機能のほとんどを発揮する。アデノシンA2b受容体(すなわちADORA2B)は、アデノシンの存在下でアデニル酸シクラーゼ活性を刺激する膜内因性タンパク質である、Gタンパク質結合アデノシン受容体である。
ある特定の実施形態では、本化合物は、グアニリルシクラーゼC(GC−C)作動薬、任意に選択的作動薬である。GC−Cは、腸上皮細胞の頂端膜において高度に濃縮されているグアニル酸シクラーゼファミリーのアイソフォームである。これはまた、急性分泌性下痢の原因である細菌分泌性の熱安定性エンテロトキシンの標的受容体である。GC−Cは、グアニル酸シクラーゼ2C、腸管内グアニル酸シクラーゼ、グアニル酸シクラーゼC受容体、及び熱安定性エンテロトキシン受容体(hSTAR)としても知られる。
Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Cys6 Cys7 Xaa8 Xaa9 Cys10Cys11 Xaa12 Xaa13 Xaa14 Cys15 Xaa16 Xaa17 Cys18 Xaa19 Xaa20 Xaa21(配列番号46)
Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Cys6 Cys7 Xaa8 Xaa9 Cys10 Cys11 Asn12 Pro13 Ala14 Cys15 Xaa16 Gly17 Cys18 Xaa19 Xaa20 Xaa21(配列番号47)
[式中、Xaa1 Xaa2 Xaa3 Xaa4 Xaa5は、Asn Ser Ser Asn Tyr(配列番号2)であるか、または欠損しているか、あるいはXaa1 Xaa2 Xaa3 Xaa4は欠損しており、Xaa5は、Asnであり、
Xaa8は、GluまたはAspであり、
Xaa9は、Leu、Ile、Val、Trp、Tyr、またはPheであり、
Xaa16は、Thr、Ala、Trpであり、
Xaa19は、Trp、Tyr、Phe、もしくはLeuであるか、または欠損しており、Xaa20Xaa21は、AspPheである]。
GC−C作動薬ペプチドの追加の例は、以下の表A3に示される。
Xaa1 Xaa2 Xaa3 Cys4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Cys12 Xaa13 Xaa14 Xaa15 Xaa16(配列番号650)
Xaa1は、任意の任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa2は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa3は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa5は、Gluであり、
Xaa6は、Tyr、Trp、Phe、またはLeuであり、
Xaa7は、Cysであり、
Xaa8は、Cys以外の任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体(任意に、20個の自然発生アミノ酸のうちのいずれか)であるか、または欠損しており、
Xaa9は、Cys以外の任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体(任意に、20個の自然発生アミノ酸のうちのいずれか)であり、
Xaa10は、ProまたはGlyであり、
Xaa11は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体(任意に、20個の自然発生アミノ酸のうちのいずれか)であり、
Xaa13は、Thr、Val、またはGlyであり、
Xaa14は、GlyまたはAlaであり、
Xaa15は、Cysであり、
Xaa16は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体(任意に、20個の自然発生アミノ酸のうちのいずれか)であるか、または欠損している。
Xaa1は、a)Ser、Asn、Tyr、Ala、Gln、Pro、Lys、Gly、もしくはThrであるか、または欠損しているか、b)LysまたはTyrに先行されるか、c)任意のアミノ酸であるか、d)欠損しているか、e)Cys以外の任意のアミノ酸であるか、あるいはf)LysまたはArgであり、
Xaa2は、a)His、Asp、Glu、Ala、Ser、Asn、Glyであるか、または欠損しているか、b)His、Asp、Glu、Ala、Ser、Asn、Gly、Proであるか、または欠損しているか、c)Asp、Glu、任意のアミノ酸であるか、または欠損しているか、d)AspまたはGluであるか、e)Cys以外の任意のアミノ酸であるか、e)Gluであるか、f)欠損しているか、g)Trp、Tyr、またはPheであるか、あるいはh)LysまたはArgであり、
Xaa3は、a)Thr、Asp、Ser、Glu、Pro、Val、もしくはLeu;AspまたはGluであるか、b)Cys以外の任意のアミノ酸であるか、c)Gluであるか、d)Thrであるか、e)Thr、Asp、Ser、Glu、Pro、Val、もしくはLeuであるか、または欠損しているか、f)Trp、Tyr、またはPheであるか、あるいはg)LysまたはArgであり、
Cys4は、任意にXaa4であり、かつCys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであり、
Xaa5は、a)任意のアミノ酸であるか、b)Glu、Asp、Gln、Gly、またはProであるか、c)Gluであるか、d)GluまたはAspであるか、e)Asp、Ile、またはGluであるか、f)任意のアミノ酸であるか、あるいはg)Cys以外の任意のアミノ酸であり、
Xaa6は、a)Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr、またはPheであるか、b)Leu、Ile、Val、Lys、Arg、Trp、Tyr、またはPhe;Leu、Ile、Lys、Arg、Trp、Tyr、またはPheであるか、c)Leu、Ile、Val、Trp、Tyr、またはPheであるか、d)Trp、Tyr、Phe、またはLeuであるか、e)Leu、Ile、またはValであるか、f)Ile、Trp、またはLeuであるか、g)Trp、Tyr、またはPheであるか、h)IleまたはLeuであるか、i)Tyrであるか、j)任意のアミノ酸であるか、k)Leu以外の任意のアミノ酸であるか、l)任意の天然もしくは非天然の芳香族アミノ酸であるか、あるいはm)Cys以外の任意のアミノ酸であり、
Xaa7は、a)Cys、Ser、またはTyr;Cysであるか、b)Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであるか、c)Serであるか、あるいはd)Cys以外のアミノ酸であり、
Xaa8は、a)Ala、Val、またはIleであるか、b)Ala、Val、Thr、Ile、Metであるか、または欠損しているか、c)任意のアミノ酸であるか、d)Valであるか、e)Cys以外の任意のアミノ酸であるか、あるいはf)欠損しており、
Xaa9は、a)任意のアミノ酸であるか、b)Phe及びTyr以外の任意のアミノ酸であるか、c)Phe、Tyr、及びTrp以外の任意のアミノ酸であるか、d)Phe、Tyr、Trp、Ile、Leu、及びVal以外の任意のアミノ酸であるか、e)Phe、Tyr、Trp、Ile、Leu、Val、及びHis以外の任意のアミノ酸であるか、i)Gln以外の任意のアミノ酸であるか、g)Lys、Arg、Phe、Tyr、及びTrp以外の任意のアミノ酸であるか、h)Lys、Arg、Phe、Tyr、Trp、Ile、Leu、及びVal以外の任意のアミノ酸であるか、i)Lys、Arg、Phe、Tyr、Trp、Ile、Leu、Val、及びHis以外の任意のアミノ酸であるか、j)任意の非芳香族アミノ酸であるか、k)欠損しているか、l)Phe、Tyr、Asn、またはTrpであるか、m)Asn、Tyr、Asp、またはAlaであるか、n)Asn、Gln、またはTyrであるか、o)PheまたはTyrであるか、p)Asnであるか、あるいはq)Cys以外の任意のアミノ酸であり、
Xaa10は、a)Ala、Pro、またはGlyであるか、b)ProまたはGlyであるか、c)Proであるか、d)Ala、Val、Met、Thr、またはIleであるか、e)任意のアミノ酸であるか、f)Valであるか、g)ValまたはProであるか、h)AlaまたはValであるか、i)Cys以外の任意のアミノ酸であるか、j)Proであるか、あるいはk)Glyであり、
Xaa11は、a)任意のアミノ酸であるか、b)Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg、またはAspであるか、c)AlaまたはGlyであるか、d)Alaであるか、e)AlaまたはValであるか、f)任意のアミノ酸であるか、g)AlaまたはAib(α−アミノイソ酪酸)であるか、h)Cys以外の任意のアミノ酸であるか、i)AlaまたはThrであるか、あるいはj)Thrであり、
Cys12は、任意にXaa12であり、かつa)Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであるか、あるいはb)Cys以外の任意のアミノ酸であり、
Xaa13は、a)Thr、Ala、Asn、Lys、Arg、またはTrpであるか、b)Thr、Ala、Lys、Arg、またはTrpであるか、c)任意のアミノ酸であるか、d)任意の非芳香族アミノ酸であるか、e)Thr、Ala、またはTrpであるか、f)Trp、Tyr、またはPheであるか、g)ThrまたはAlaであるか、h)任意のアミノ酸であるか、i)Thrであるか、j)Cys以外の任意のアミノ酸であるか、k)Thr、Val、またはGlyであるか、l)ThrまたはValであるか、m)ThrまたはGlyであるか、n)ValまたはThrであるか、o)Valであるか、p)Thrであるか、あるいはq)Glyであり、
Xaa14は、a)Gly、Pro、またはAlaであるか、b)Glyであるか、c)任意のアミノ酸であるか、d)Gly、Ala、またはSerであるか、e)GlyまたはAlaであるか、f)Cys以外の任意のアミノ酸であるか、あるいはg)Alaであり、
Xaa15は、a)Cys、Tyrであるか、または欠損しているか、b)Cysであるか、c)Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、Gluであるか、あるいはd)Cys以外の任意のアミノ酸であるか、または欠損しており、
Xaa16は、a)Trp、Tyr、Phe、Asn、lie、Val、His、またはLeuであるか、b)Trp、Tyr、Phe、Asn、またはLeuであるか、c)Tip、Tyr、Phe、またはLeuであるか、d)Trp、Tyr、またはPheであるか、e)Leu、Ile、またはValであるか、f)His、Leu、またはSerであるか、g)TyrまたはLeu;LysまたはArgであるか、h)Hisであるか、i)任意のアミノ酸であるか、j)Leuであるか、または欠損しているか、k)Trp、Tyr、Phe、Lys、Argであるか、または欠損しているか、l)欠損しているか、m)Cys以外の任意のアミノ酸であるか、あるいはn)Tyrである。
Xaa1は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa2は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa3は、任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa4は、Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであり、
Xaa5は、Gluであり、
Xaa6は、Tyr、Trp、Phe、またはLeuであり、
Xaa7は、Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであり、
Xaa8は、Cys以外の任意の天然もしくは非天然のアミノ酸またはアミノ酸類似体であるか、または欠損しており、
Xaa9は、任意のアミノ酸であり、
Xaa10は、ProまたはGlyであり、
Xaa11は、任意のアミノ酸であり、
Xaa12は、Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであり、
Xaa13は、Thr、Val、またはGlyであり、
Xaa14は、GlyまたはAlaであり、
Xaa15は、Cys、Mpt(メルカプトプロリン)、Pen(ペニシラミン)、Dpr(ジアミノプロピオン酸)、Asp、またはGluであり、
Xaa16は、任意のアミノ酸であるか、または欠損している。
Xaa1は、Asn、任意のアミノ酸であるか、または欠損しており、
Xaa2は、Asp、Glu、任意のアミノ酸であるか、または欠損しており、
Xaa3は、AspまたはGluであり、
Xaa5は、任意のアミノ酸またはGluであり、
Xaa6は、任意のアミノ酸またはLeuであり、
Xaa7は、Cysであり、
Xaa8は、任意のアミノ酸またはValであり、
Xaa9は、Asn、Gln、またはTyrであり、
Xaa10は、任意のアミノ酸またはValであり、
Xaa11は、任意のアミノ酸またはAlaであり、
Xaa13は、任意のアミノ酸またはThrであり、
Xaa14は、任意のアミノ酸またはGlyであり、
Xaa15は、Cysであり、
Xaa16は、任意のアミノ酸、Leuであるか、または欠損している。
Xaa1は、Ser、Asn、Tyr、Ala、Gln、Pro、Lys、Gly、もしくはThrであるか、または欠損しており、
Xaa2は、His、Asp、Glu、Ala、Ser、Asn、もしくはGlyであるか、または欠損しており、
Xaa3は、Thr、Asp、Ser、Glu、Pro、Val、もしくはLeuであるか、または欠損しており、
Xaa5は、Asp、Ile、またはGluであり、
Xaa6は、Ile、Trp、またはLeuであり、
Xaa7は、Cys、Ser、またはTyrであり、
Xaa8は、Ala、Val、Thr、Ile、もしくはMetであるか、または欠損しており、
Xaa9は、a)Phe及びTyr以外の任意のアミノ酸であるか、b)Phe、Tyr、及びTrp以外の任意のアミノ酸であるか、c)Phe、Tyr、Trp、Ile、Leu、及びVal以外の任意のアミノ酸であるか、d)Phe、Tyr、Trp、Ile、Leu、Val、及びHis以外の任意のアミノ酸であるか、d)任意の非芳香族アミノ酸であるか、またはe)欠損しているかのいずれかであり、
Xaa10は、Ala、Val、Met、Thr、またはIleであり、
Xaa11は、AlaまたはValであり、
Xaa13は、AlaまたはThrであり、
Xaa14は、Gly、Ala、またはSerであり、
Xaa15は、Cys、Tyrであるか、または欠損しており、
Xaa16は、a)キモトリプシン切断部位を発生させるTrp、Tyr、もしくはPheであるか、b)トリプシン切断部位を発生させるLysもしくはArgであるか、c)欠損しているか、またはd)HisもしくはLeuもしくはSerである。
Asn1 Xaa2 Xaa3 Xaa4 Glu5 Leu6 Xaa7 Val8 Asn9 Xaa10 Xaa11 Xaa12 Thr13 Xaa14 Xaa15 Leu16(配列番号670)
[式中、Xaa2は、AspまたはGluであり、
Xaa3は、AspまたはGluであり、
Xaa4は、CysまたはMpt(メルカプトプロリン)またはPen(ペニシラミン)またはDpr(ジアミノプロピオン酸)またはAspまたはGluであり、
Xaa7は、CysまたはMpt(メルカプトプロリン)またはPen(ペニシラミン)またはDpr(ジアミノプロピオン酸)またはAspまたはGluであり、
Xaa10は、ValまたはProであり、
Xaa11は、AlaまたはAib(α−アミノイソ酪酸)であり、
Xaa12は、CysまたはMpt(メルカプトプロリン)またはPen(ペニシラミン)またはDpr(ジアミノプロピオン酸)またはAspまたはGluであり、
Xaa14は、GlyまたはAlaであり、
Xaa15は、CysまたはMpt(メルカプトプロリン)またはPen(ペニシラミン)またはDpr(ジアミノプロピオン酸)またはAspまたはGluである]。
ヒトウログアニリン類似体の具体例は、以下の表A7に提供される。
ある特定の実施形態では、本化合物は、可溶性グアニル酸シクラーゼ(sGC)作動薬である。グアニンヌクレオチジル(グアニリル;グアニル酸塩)シクラーゼ(GC)は、種々の細胞刺激に応答して、GTPを二次メッセンジャーである環状GMP(cGMP)に転換する、広く分布するシグナル伝達酵素である。膜結合性及び可溶性の両方のグアニル酸シクラーゼが存在し、これら両方がcGMPの細胞内濃度を上昇させることができる。
ある特定の実施形態では、本化合物は、アデニル酸シクラーゼ作動薬、任意に選択的作動薬である。アデニル酸シクラーゼ(またはアデニリルシクラーゼ)は、3’,5’−環状AMP(cAMP)及びピロリン酸塩へのATPの転換を触媒する酵素の一種を指す。二価カチオン(例えばMg)が、多くの場合、この酵素活性に関与する。アデニル酸シクラーゼによって産生されるcAMPは、転写因子または他の酵素(例えば、cAMP依存性キナーゼ)を含む、特異的cAMP結合タンパク質を介する制御シグナルとして機能する。
ある特定の実施形態では、本化合物は、イミダゾリン−1受容体作動薬、任意に選択的作動薬である。イミダゾリン受容体は、クロニジン、イダゾキサン、及び他のイミダゾールの非アドレナリン性の高親和性結合部位のファミリーを含む。イミダゾリンの交感神経抑制作用を媒介して血圧を低下させるI1受容体、モノアミンオキシダーゼのアロステリック結合部位であり、疼痛の調節及び神経保護に関与するI2受容体、ならびに膵β細胞からのインスリン分泌を制御するI3受容体という、3つの種類のイミダゾリン受容体が存在する。いくつかの態様では、本化合物は、例えば、イミダゾリン−2及び/またはイミダゾリン−3受容体と比べて選択的なイミダゾリン−1受容体作動薬である。
ある特定の実施形態では、本化合物は、コリン作動薬、任意に選択的コリン作動薬である。コリン作動薬の例としては、アセチルコリンの産生または放出を刺激する間接的コリン作動薬(例えば、アステチルコリンエステラーゼ阻害薬)、及び1つ以上のアセチルコリン受容体に結合し、かつそれを刺激する直接的コリン作動薬が挙げられる。神経伝達物質であるアセチルコリン(2−アセトキシ−N,N,N−トリメチルエタンアミニウム)は、酢酸及びコリンのエステルである。アセチルコリン受容体の一般例としては、ニコチン性アセチルコリン受容体及びムスカリン性アセチルコリン受容体が挙げられる。ニコチン性アセチルコリン受容体は、5つのタンパク質サブユニットから成るリガンド開口型イオンチャネルである。
ある特定の実施形態では、本化合物は、E型プロスタノイド受容体4(EP4)作動薬(またはプロスタグランジンEP4受容体作動薬)、任意に選択的作動薬である。EP4受容体は、アデニル酸シクラーゼの刺激及び細胞内cAMPレベルの上昇を引き起こすGαsタンパク質結合受容体として初めに説明された。cAMP形成を刺激したプロスタグランジンE2(PGE2)受容体としてはじめてクローン化されたとき、EP4受容体は「EP2」と命名された。しかしながら、ブタプロストに感応性のある別のcAMP刺激性PGE2受容体が発見され、血管弛緩を媒介したブタプロスト非感応性受容体は「EP4」と改名された。これは、PGE2について特定された4つの受容体のうちの1つである。
ある特定の実施形態では、本化合物は、ドパミンD−1受容体作動薬、任意に選択的作動薬である。ドパミンD1 Gタンパク質結合受容体は、ドパミン受容体ファミリーの中で最も高度に発現されるドパミン受容体サブタイプである。これは、アデニル酸シクラーゼを刺激し、環状AMP依存性タンパク質キナーゼを活性化させる。
ある特定の実施形態では、本化合物は、メラトニン受容体作動薬、任意に選択的作動薬である。メラトニン受容体は、松果体ホルモンであるメラトニンに結合する、高親和性Gタンパク質結合受容体のファミリーを指す。Reppert,Biol Rhythms.12:528−31,1997を参照されたい。
ある特定の実施形態では、本化合物は、5HT4受容体作動薬、任意に選択的作動薬である。5−ヒドロキシトリプタミン受容体4(5HT4)は、セロトニン(5−ヒドロキシトリプタミン、すなわち5−HT)または他の作動薬に応答してcAMP産生を刺激する、Gタンパク質結合セロトニン受容体である。
いくつかの実施形態では、本化合物は、心房性ナトリウム利尿ペプチド(NP)受容体作動薬である。NP受容体は、細胞内グアニリルシクラーゼ(GC)活性を有する単一の膜貫通触媒受容体である。NP受容体の3つのアイソフォームである、NPR1、NPR2、及びNPR3が存在する。これらの受容体は、触媒ドメイン及び制御ドメイン、ならびに分岐リガンド結合ドメインを保存している。
いくつかの実施形態では、本化合物は、炭酸脱水酵素阻害薬である。上皮細胞への重炭酸塩取り込みは、CO2拡散と、その後の細胞の炭酸脱水酵素(CA)によるHCO3 −及びH+への転換によって発生する。次に重炭酸塩は、アニオン交換によって頂端膜を横断して分泌される。CAは、CO2を水和させてHCO3 −及びH+を生成する酵素であり、十二指腸の上皮細胞を含むほとんどの組織内に存在する。例えば、Kaunitz and Akiba,2006を参照されたい。この内因的に生成されるHCO3 −は、輸送される重炭酸塩の重要な源である。
いくつかの実施形態では、本化合物は、ホスホジエステラーゼ阻害薬である。ホスホジエステラーゼ(PDE)は、アデノシン内の3’環状リン酸塩結合及び/またはグアニン3’,5’環状一リン酸塩(cAMP及び/またはcGMP)の加水分解を選択的に触媒する、関連するホスホヒドロリアーゼのファミリーである。これらは、それら二次メッセンジャーの分解の速度を制御することによって、それらの細胞レベル、局在化、及びその作用の持続時間を制御する。
ある特定の実施形態では、本化合物は、腺腫において下方制御される交換輸送体(DRA)とも称される、塩素イオン/重炭酸イオン交換輸送体であるSLC26A3の作動薬である。腸内のDRAの1つの非限定的な機能は、管腔の塩素イオンを吸収し、重炭酸イオンを分泌することである。DRAの薬理学的刺激は、本明細書に記載されるように、例えばUWLのpHを増加させることによって、pHiを低減させ、リン酸塩低下作用をもたらすと予想される。
A.胃腸管に局在化可能な化合物の物理特性及び性能特性
本明細書に記載される化合物のうちある特定のものは、ヒトまたは動物の対象の胃腸内腔内で実質的に活性または局在性であるように設計される。「胃腸内腔」という用語は、本明細書において「内腔」という用語と互換的に使用され、対象の胃腸上皮細胞の頂端膜で区切られる胃腸管(胃腸(GI)管、腸とも称され得る)内の空間または空洞を指す。いくつかの実施形態では、本化合物は、(胃腸(GI)上皮としても知られる)胃腸管の上皮細胞の層を通して吸収されない。「胃腸粘膜」は、胃腸内腔を身体の残部から分離する細胞の層(複数可)を指し、小腸の粘膜などの胃及び腸管の粘膜を含む。本明細書において使用される場合、「胃腸上皮細胞」または「腸上皮細胞」は、例えば、胃の上皮細胞、腸上皮細胞、結腸上皮細胞などを含む、胃腸管の内腔に面する胃腸粘膜の表面上の任意の上皮細胞を指す。
この点で、種々の実施形態では、本化合物が実質的に全身で生体利用不可能である能力は、化合物の電荷、大きさ、及び/または他の物理化学的パラメータ(例えば、極性表面積、その中の水素結合供与体及び/または受容体の数、自由に回転可能な結合の数など)に基づくことに留意されたい。より具体的には、化合物の吸収の特性は、薬物動態の原理を適用すること、例えば、「ルールオブファイブ」としても知られるリピンスキーの法則を適用することによって選択され得ることに留意されたい。法則ではなくむしろ一式の指針であるが、リピンスキーは、ある特定の閾値を超える(i)分子量、(ii)いくつかの水素結合供与体、(iii)いくつかの水素結合受容体、及び/または(iv)水/オクタノール分配係数(Moriguchi対数P)を有する小分子薬物は、一般的に著しい全身濃度を示さない(すなわち、一般的にいかなる著しい度合にも吸収されない)ことを示す。(例えば、参照により本明細書に組み込まれるLipinski et al.,Advanced Drug Delivery Reviews,46:3−26,2001を参照されたい。)したがって、実質的に全身で生体利用不可能な化合物は、リピンスキーの閾値のうちの1つ以上を超える分子構造を有するように設計され得る。(参照により全体が本明細書に組み込まれる、Lipinski et al.,Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings,Adv.Drug Delivery Reviews,46:3−26,2001、及びLipinski,Drug−like Properties and the Causes of Poor Solubility and Poor Permeability,J.Pharm.& Toxicol.Methods,44:235−249,2000も参照されたい。
いくつかの実施形態では、本明細書に詳述される実質的に全身で生体利用不可能な化合物は、単独、または1つ以上の追加の薬学的に活性な化合物もしくは薬剤との組み合わせのいずれかで、それを必要とする対象に(例えば、経腸的に)投与されると、本化合物のリン酸イオン(Pi)輸送もしくは取り込みの阻害濃度であるIC50とほぼ同じかまたはそれ未満である、Cmaxとして定義される血清中で検出される最大濃度を示す。例えばいくつかの実施形態では、Cmaxは、Pi輸送もしくは取り込みを阻害するように、IC50より約または少なくとも約5%、10%、20%、30%、40%、50%、60%、70%、80%、90%、もしくは100%低い。いくつかの実施形態では、Cmaxは、Pi輸送もしくは取り込みを阻害するように、IC50の約0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9倍である。
投与の目的のために、本発明の化合物は、未加工の化学物質として患者もしくは対象に投与され得るか、または薬学的組成物として製剤化され得る。本発明の薬学的組成物は、概して、本発明の化合物、及び薬学的に許容される担体、希釈剤、または賦形剤を含む。本化合物は、本明細書に記載されるように、目的の特定の疾患または状態を治療するのに有効な量で組成物中に存在し、好ましくは対象に許容される毒性を有する。化合物(複数可)の活性は、例えば、本明細書及び以下の実施例に記載されるように、当業者によって決定され得る。適切な濃度及び薬用量は、当業者によって容易に決定され得る。
胃腸管内のリン酸塩取り込みを阻害し得る化合物の創薬に関する方法も含まれる。特定の実施形態は、腸細胞培養物などの細胞培養物または哺乳動物の細胞株を含む細胞株を用いる、薬物スクリーニングのインビトロ方法を含む。
「アミノ」は、−NH2ラジカルを指す。
(i)特に哺乳動物が疾患または状態にかかりやすい状態だがそれを有すると未だ診断されていないとき、そのような哺乳動物におけるその状態の発症を防止すること、
(ii)疾患または状態を阻害すること、すなわち、その発達を停止させること、
(iii)疾患または状態を緩和すること、すなわち、疾患または状態の退行を引き起こすこと、あるいは
(iv)疾患または状態に起因する症状を緩和すること、すなわち、根底にある疾患または状態に対処せずに疼痛を緩和すること、を含む。本明細書において使用される場合、「疾患」及び「状態」という用語は、互換的に使用され得るか、あるいは、特定の病弊または状態が既知の原因物質を有しない(そのため病因が未だ究明されていない)場合があり、したがって疾患としてではなく、多かれ少なかれ一式の特定の症状が臨床医によって特定されている望ましくない状態または症候群としてしか認識されていないという点で、異なっていてもよい。
実施例
細胞内pHの増加は、細胞内のリン酸塩取り込みの減少をもたらす
実験を行って、ヒト胎児由来腎臓細胞(HEK−293細胞)内の細胞内pHの変化とリン酸イオン(Pi)の取り込みの変化との間の関係を試験した。
グアニル酸シクラーゼC(GC−C)受容体作動薬は、リン酸塩吸収を減少させる
実験を行って、グアニル酸シクラーゼC(GC−C)受容体作動薬が、33P取り込みによって測定されたときの小腸内のリン酸塩吸収/取り込みを減少させ得るかを判定した。以下に示されるように、33P及びリナクロチドをラットに同時に投与した。
1.ビヒクル(N=5/群)
2.0.1mg/kgのリナクロチド(N=6/群)
3.0.3mg/kgのリナクロチド(N=4/群)
I1受容体作動薬及びアデニル酸シクラーゼ作動薬は、リン酸塩吸収を減少させる
実験を行って、他の種類の薬物が、33P取り込みによって測定されたときの小腸内のリン酸塩吸収/取り込みを減少させ得るかを判定した。以下に示されるように、33P及びイミダゾリンサブタイプ1(I1)受容体作動薬(モクソニジン)またはアデニル酸シクラーゼ作動薬(水溶性フォルスコリン類似体であるNKH477)のいずれかをラットに同時に投与した。
1.ビヒクル
2.2mg/kgのモクソニジン
3.6mg/kgのモクソニジン
4.1mg/kgのNKH477
5.3mg/kgのNKH477
A2B作動薬及びP2Y2作動薬は、リン酸塩吸収を減少させる
実験を行って、異なる機構による細胞内カルシウム(Ca++)の増加が、33P取り込みによって測定されたときの小腸内のリン酸塩吸収も減少させ得るかを判定した。以下に示されるように、33P及び試験化合物をラットに同時に投与した。
1.ビヒクル、n=6
2.10mg/kgのBAY 60−6583(アデノシンA2B作動薬)
3.15mg/kgのUp4U(P2Y2受容体作動薬)
ラットの急性リン酸塩取り込みに対する薬力学的作用
化合物を、ラットの消化管への投与の後に、循環している放射標識化されたリン酸塩の出現を低減させる能力について試験した。ラットの血液中の放射標識化されたリン酸塩のトレーサーの蓄積の速度を、胃腸管からのリン酸塩食の腸管内吸収速度の代理として計った。この目的のために、実施例の化合物と合わせたリン酸塩トレーサー食のラットへの胃内共投与の後に、循環している放射標識化されたリン酸塩を監視した。しかしながら、試験した化合物のうちのいくつかは、推定上の胃腸運動性作用を有する(例えば、胃内容排出を遅延させる)、または意図的に胃腸管内で化学的に不安定であるなど、このアッセイを妨げ得る特性を潜在的に有したため、リン酸塩トレーサーのボーラスの直接的な十二指腸内投与も折々行った。
Ussingチャンバ
麻酔された動物から十二指腸及び空腸の断片をただちに除去し、腸間膜線に沿って開き、粘膜表面最上部とともにPyrexプレート上に固定する。上皮組織を筋層からストリッピングし、コンピュータ制御されたUssingチャンバ(National Physiology Instrument、California)上に100mm2の露出面積で設置する。この組織の両面を、(ミリモル/Lで)NaCl(125.4)、KCl(5.4)、CaC12(1.2)、NaHCO3(21)、NaHPO(0.3)、NaH2PO4(1.2)を含有する13mLの等張緩衝溶液(pH6.0またはpH7.4)とともにインキュベートする。流束測定の開始及び終了時の組織の機能的生存能及び整合性は、テオフィリン(10mM漿膜)またはグルコース(10mM粘膜)またはL−アラニン(5mM粘膜)のいずれかに応答する短絡電流(Isc)の測定で確かになるであろう。
インビトロ−エクスビボアッセイ
ペントバルビタールナトリウムで麻酔された動物から十二指腸及び空腸の断片(5cm)を除去し、氷冷の0.9%の食塩水で洗い流し、ガラス棒上で裏返す。試料を棒上にしっかりと設置し、次に、mM単位でヒドロキシエチルピペラジン−N’−2−エタンスルホン酸(16)、グルコース(10)、KCl(3.5)、MgSO4(10)、CaCl2(1)、NaCl(125)を含有する、pH7.4もしくは6.0の酸素化緩衝液中で、5分間37℃でプレインキュベートし、続いて100mMの33Pi(33Pi特異的活性、1.85MBq/mL)及び試験化合物を含有する同じ緩衝液中で2分間インキュベートする。粘膜表面における静水層の作用を最小限に抑えるために磁気撹拌子(magnetic flea)を使用して、緩衝液を急速に撹拌する。
標的ベースのスクリーニングアッセイ
腸受容体の活性化は、(例えば、腸の管腔膜の局在性pHを変更することによって)リン酸塩吸収の直接的阻害または間接的阻害のいずれかを引き起こすシグナル伝達をもたらし得る。これらの標的と相互作用する化合物の能力の測定は、目的の標的を異種性に発現する市販の細胞株を使用して達成され得る。これらの細胞株は、Perkin ElmerまたはMultispanなどの会社から一般的に入手可能である。代替的に、目的の標的を発現する初代細胞も一般的に使用される。
腸管内のナトリウム及びリン酸塩吸収の阻害
腸管内腔からのリン酸塩の吸収を阻害する、選択された実施例の化合物の能力を評価するために、ラットにおいてリン酸塩の摂取及び排泄の均衡を測定する。8週齢のSprague DawleyラットをCharles River Laboratories(Hollister,CA)から購入し、食物及び水を自由に与えて、少なくとも6日間順化させる。この時間の間、及び研究全体にわたって、標準的飼料(Harlan Teklad、Madison,WI、2018 Teklad Global 18% Protein Rodent Diet)、または0.6%のCa及び0.35もしくは0.6%のリンから成る精製卵白合成飼料(Harlan Teklad、それぞれTD.84122及びTD.130318)をラットに給餌してよい。
ラット慢性腎疾患(CKD)モデルにおける作用。
多くの場合後期のCKDに関連する軟組織石灰化に影響する、選択された実施例の化合物の能力を評価するために、5/6腎摘除(5/6Nx)ラットモデルを用いて、病的状態におけるミネラルの恒常性を検査する。CKDの種々の態様を研究するために一般的に使用されるモデルである5/6Nxラットは、食事性リン酸塩の負荷を受けない限り、通常は高リン血症ではない(Shobeiri et.al.,Am J Nephrol.31:471−481,2010,Vascular Calcification in Animal Models of CKD:A Reviewを参照されたい)。したがって、これらの動物において効率的かつ定常なリン血性の血管石灰化の進行を確かにするために、Lopezのグループによって開発されたプロトコルから適合された、飼料中の向上した生体利用能のリン酸塩とビタミンD3処置の組み合わせを実施する(Lopez et al.,J Am Soc Nephrol.17:795−804,2006.Calcimimetic R−568 Decreases Extraosseous Calcifications in Uremic Rats Treated with Calcitriolを参照されたい)。
Claims (93)
- リン酸塩低下を必要とする患者の胃腸管内のリン酸塩取り込みを阻害するための方法であって、グアニル酸シクラーゼC受容体(GC−C)作動薬化合物を前記患者に投与することを含み、前記GC−C作動薬化合物が、それを必要とする前記患者に投与されると、胃腸管内でその中のリン酸イオン(Pi)の輸送を阻害するように実質的に活性である、前記方法。
- リン酸塩低下を必要とする患者の胃腸管内のリン酸塩取り込みを阻害するための方法であって、NHE3に結合しない化合物を前記患者に投与することを含み、前記化合物が、それを必要とする前記患者に投与されると、胃腸管内でその中のリン酸イオン(Pi)の輸送を阻害するように実質的に活性である、前記方法。
- 前記化合物が、小腸内の上皮横断pH勾配(cross−epithelial pH gradient)(CEPG)を減少させ、前記CEPGが、(i)小腸の表面の上皮細胞の、任意に上皮細胞の亜頂端表面における細胞質と、(ii)小腸の頂端表面における不撹拌層との間のpHの差として定義され、前記化合物が、それを必要とする前記患者に投与されると、胃腸管内でその中のリン酸イオン(Pi)の輸送を阻害するように実質的に活性である、請求項2に記載の前記方法。
- 前記化合物が、小腸、任意に空腸内の水吸収を減少させ、前記化合物が、それを必要とする患者に投与されると、胃腸管内でその中のリン酸イオン(Pi)の輸送を阻害するように実質的に活性である、請求項2に記載の前記方法。
- 前記化合物が、小腸内のCEPGを減少させ、水吸収を減少させる、請求項2〜4のいずれか1項に記載の前記方法。
- 前記化合物が、小腸内の水吸収を著しく減少させることなく小腸内のCEPGを減少させる、請求項2または3に記載の前記方法。
- 前記化合物が、小腸内のCEPGを著しく減少させることなく、任意に、小腸内の重炭酸塩分泌を著しく刺激することなく、かつ/または酸分泌を阻害することなく小腸内の水吸収を減少させる、請求項2または4に記載の前記方法。
- 前記方法が、
(a)高リン血症、任意に食後高リン血症を治療するための方法、
(b)腎疾患、任意に慢性腎疾患(CKD)または末期腎疾患(ESRD)を治療するための方法、
(c)血清クレアチニンレベルを低減させるための方法、
(d)タンパク尿を治療するための方法、
(e)腎代替療法(RRT)、任意に透析までの時間を遅らせるための方法、
(f)FGF23レベルを低減させるための方法、
(g)活性型ビタミンDの高リン血症作用を低減させるための方法、
(h)副甲状腺機能亢進症、任意に続発性副甲状腺機能亢進症を軽減させるための方法、
(i)血清副甲状腺ホルモン(PTH)を低減させるための方法、
(j)任意に食後血清リンによって誘導される、内皮障害を改善するための方法、
(k)血管石灰化、任意に内膜局在性血管石灰化を低減させるための方法、
(l)尿中亜リン酸を低減させるための方法、
(m)血清リンレベルを正常化するための方法、
(n)高齢患者のリン負荷を低減させるための方法、
(o)食事性リン酸塩取り込みを減少させるための方法、
(p)腎肥大を低減させるための方法、及び
(q)心肥大を低減させるための方法、のうちの1つ以上から選択される方法をもたらす、請求項1〜7のいずれか1項に記載の前記方法。 - 前記化合物が、小腸の表面の上皮細胞の、任意に上皮細胞の亜頂端表面における細胞内pHを減少させる、請求項2〜6または8のいずれか1項に記載の前記方法。
- 前記化合物が、小腸の頂端表面における不撹拌層のpHを増加させる、請求項2〜6または8のいずれか1項に記載の前記方法。
- 前記化合物が、(a)小腸内の重炭酸塩分泌を刺激するか、または(b)小腸内の酸分泌を阻害するか、または(c)小腸内の重炭酸塩分泌を刺激し、かつ酸分泌を阻害する、請求項2〜6または8のいずれか1項に記載の前記方法。
- 前記化合物が、小腸の表面の上皮細胞の1つ以上の細胞内二次メッセンジャーを増加させる、請求項2〜6または8のいずれか1項に記載の前記方法。
- 前記1つ以上の細胞内二次メッセンジャーが、Ca++、環状アデノシン一リン酸塩(cAMP)、及び環状グアノシン一リン酸塩(cGMP)から選択される、請求項12に記載の前記方法。
- 前記化合物が、前記患者に経腸投与されると実質的に全身で生体利用不可能である、請求項1〜13のいずれか1項に記載の前記方法。
- 前記化合物が、胃腸管の上皮に対して実質的に不透過性である、請求項14に記載の前記方法。
- 前記化合物が、胃腸管の上皮に対して実質的に透過性である、請求項14に記載の前記方法。
- それを必要とする前記患者への投与が、(a)血清リン濃度もしくはレベルを正常な血清リンレベルの約150%以下に低減させ、かつ/または(b)食事性亜リン酸の取り込みを無処置状態と比べて少なくとも約10%低減させる、請求項1〜16のいずれか1項に記載の前記方法。
- それを必要とする前記患者への投与が、糞便中排泄におけるリン酸塩レベルを無処置状態と比べて少なくとも約10%上昇させる、請求項1〜17のいずれか1項に記載の前記方法。
- それを必要とする前記患者への投与が、尿中リン酸塩濃度またはレベルを無処置状態と比べて少なくとも約10%低減させる、請求項1〜18のいずれか1項に記載の前記方法。
- それを必要とする前記患者が、ESRDを有し、前記患者への投与が、血清リン濃度またはレベルを無処置状態と比べて少なくとも約10%低減させる、請求項1〜19のいずれか1項に記載の前記方法。
- それを必要とする前記患者が、CKDを有し、前記患者への投与が、FGF23レベル及び血清インタクト副甲状腺ホルモン(iPTH)レベルを無処置状態と比べて少なくとも約10%低減させる、請求項1〜20のいずれか1項に記載の前記方法。
- 前記化合物が、グアニル酸シクラーゼC受容体(GC−C)作動薬、P2Y作動薬、アデノシンA2b受容体作動薬、可溶性グアニル酸シクラーゼ作動薬、アデニル酸シクラーゼ受容体作動薬、イミダゾリン−1受容体作動薬、コリン作動薬、プロスタグランジンEP4受容体作動薬、ドパミンD1作動薬、メラトニン受容体作動薬、5HT4作動薬、心房性ナトリウム利尿ペプチド受容体作動薬、炭酸脱水酵素阻害薬、ホスホジエステラーゼ阻害薬、及び腺腫において下方制御される交換輸送体(Down−Regulated in Adenoma)(DRAまたはSLC26A3)作動薬のうちの1つ以上から選択される、請求項2〜21のいずれか1項に記載の前記方法。
- 前記GC−C作動薬が、ペプチド、任意に細菌性熱安定性エンテロトキシン、グアニリン、プログアニリン、ウログアニリン、プロウログアニリン、リンホグアニリン、または前述のもののうちのいずれかの変異体もしくは類似体である、請求項1または22に記載の前記方法。
- 前記GC−C作動薬ペプチドが、アミノ酸配列(I):Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Cys6 Cys7 Xaa8 Xaa9 Cys10 Cys11 Xaa12 Xaa13 Xaa14 Cys15 Xaa16 Xaa17 Cys18 Xaa19 Xaa20 Xaa21(配列番号1)を含み、Xaa1 Xaa2 Xaa3 Xaa4 Xaa5が、Asn Ser Ser Asn Tyr(配列番号2)であるか、または欠損しているか、あるいはXaa1 Xaa2 Xaa3 Xaa4が欠損している、請求項23に記載の前記方法。
- Xaa5が、Asn、Trp、Tyr、Asp、またはPheである、請求項24に記載の前記方法。
- Xaa5が、ThrまたはIleである、請求項24に記載の前記方法。
- Xaa5が、Tyr、Asp、またはTrpである、請求項24に記載の前記方法。
- Xaa8が、Glu、Asp、Gln、Gly、またはProである、請求項24に記載の前記方法。
- Xaa9が、Leu、Ile、Val、Ala、Lys、Arg、Trp、Tyr、またはPheである、請求項24に記載の前記方法。
- Xaa9が、Leu、Ile、Val、Lys、Arg、Trp、Tyr、またはPheである、請求項24に記載の前記方法。
- Xaa12が、Asn、Tyr、Asp、またはAlaである、請求項24に記載の前記方法。
- Xaa13が、Ala、Pro、またはGlyである、請求項24に記載の前記方法。
- Xaa14が、Ala、Leu、Ser、Gly、Val、Glu、Gln、Ile、Leu、Lys、Arg、またはAspである、請求項24に記載の前記方法。
- Xaa16が、Thr、Ala、Asn、Lys、Arg、またはTrpである、請求項24に記載の前記方法。
- Xaa17が、Gly、Pro、またはAlaである、請求項24に記載の前記方法。
- Xaa19が、Trp、Tyr、Phe、Asn、またはLeuである、請求項24に記載の前記方法。
- Xaa19が、LysまたはArgである、請求項24に記載の前記方法。
- Xaa20 Xaa21がAspPheであるか、あるいはXaa20がAsnまたはGluであり、Xaa21が欠損している、請求項24に記載の前記方法。
- Xaa19 Xaa20 Xaa21が欠損している、請求項24に記載の前記方法。
- 前記GC−C作動薬ペプチドが、アミノ酸配列Asn Ser Ser Asn Tyr Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(配列番号3)、あるいは1個、2個、3個、4個、もしくは5個の欠失、挿入、及び/または置換を有するその変異体を含む、請求項24に記載の前記方法。
- 前記ペプチドが、アミノ酸配列Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr(配列番号4)、あるいは1個、2個、3個、4個、もしくは5個の欠失、挿入、及び/または置換を有するその変異体を含む、請求項24に記載の前記方法。
- 前記GC−C作動薬ペプチドが、アミノ酸配列(III):Xaa1 Xaa2 Xaa3 Cys4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10 Xaa11 Cys12 Xaa13 Xaa14 Xaa15 Xaa16(配列番号5)を含み、Xaa1が、Ser、Asn、Tyr、Ala、Gln、Pro、Lys、Gly、もしくはThrであるか、または欠損しており、Xaa2が、His、Asp、Glu、Ala、Ser、Asn、Glyであるか、または欠損しており、Xaa3が、Thr、Asp、Ser、Glu、Pro、Val、またはLeuであり、Xaa5が、Asp、Ile、またはGluであり、Xaa6が、Ile、Trp、またはLeuであり、Xaa7が、Cys、Ser、またはTyrであり、Xaa8が、Ala、Val、Thr、Ile、Metであるか、または欠損しており、Xaa9が、Phe、Tyr、Asn、またはTrpであり、Xaa10が、Ala、Val、Met、Thr、またはIleであり、Xaa11が、AlaまたはValであり、Xaa13が、ThrまたはAlaであり、Xaa14が、Gly、Ala、またはSerであり、Xaa15が、Cys、Tyrであるか、または欠損しており、Xaa16が、His、Leu、またはSerである、請求項23に記載の前記方法。
- 前記ペプチドが、アミノ酸配列Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu(配列番号6)、あるいは1個、2個、3個、4個、もしくは5個の欠失、挿入、及び/または置換を有するその変異体を含む、請求項42に記載の前記方法。
- 前記P2Y作動薬が、図4または図5A〜5C中の化合物から選択される、請求項22に記載の前記方法。
- 前記アデノシンA2b受容体作動薬が、図6A〜6C中の化合物から選択される、請求項22に記載の前記方法。
- 前記可溶性グアニル酸シクラーゼ作動薬が、図9A〜9L中の化合物から選択される、請求項22に記載の前記方法。
- 前記アデニル酸シクラーゼ受容体作動薬が、図10中の化合物から選択される、請求項22に記載の前記方法。
- 前記イミダゾリン−1受容体作動薬が、モクソニジン及び図11中の化合物から選択される、請求項22に記載の前記方法。
- 前記コリン作動薬が、図12中の化合物から選択される、請求項22に記載の前記方法。
- 前記プロスタグランジンEP4受容体作動薬が、PGE2またはその類似体/誘導体、及び図7または図13中の化合物から選択される、請求項22に記載の前記方法。
- 前記ドパミンD1作動薬が、図14中の化合物から選択される、請求項22に記載の前記方法。
- 前記メラトニン受容体作動薬が、メラトニン及び図15中の化合物から選択される、請求項22に記載の前記方法。
- 前記5HT4作動薬が、セロトニン及びその類似体、プルカロプリド、メトクロプラミド、クレオボプリド、モサプリド、プルカロプリド、レンザプリド、テガセロッド、ザコプリド、ノルシサプリド、ナロノプリド、ならびにベルセトラグから選択される、請求項22に記載の前記方法。
- 前記心房性ナトリウム利尿ペプチド受容体作動薬が、Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Ile Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr(配列番号7)、Cys Phe Gly Gly Arg Ile Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys(配列番号8)、及びSer Ser Cys Phe Gly Gly Arg Ile Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg(配列番号9)から選択されるアミノ酸配列(1個、2個、3個、4個、もしくは5個の欠失、挿入、及び/または置換を有するそれらの変異体を含む)を含むか、またはそれから成る、請求項22に記載の前記方法。
- 前記炭酸脱水酵素阻害薬が、図17中の化合物から選択される、請求項22に記載の前記方法。
- 前記ホスホジエステラーゼ阻害薬が、図18中の化合物から選択される、請求項22に記載の前記方法。
- 前記DRA作動薬が、図21A〜Bから選択される、請求項22に記載の前記方法。
- 前記化合物が、前記患者に経腸投与されると実質的に全身で生体利用不可能であり、(i)少なくとも約200Å2のtPSAを有する、請求項1〜57のいずれか1項に記載の前記方法。
- 前記化合物が、少なくとも約250Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約270Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約300Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約350Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約400Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約500Å2のtPSAを有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約500Daの分子量を有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約1000Daの分子量を有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約2500Daの分子量を有する、請求項58に記載の前記方法。
- 前記化合物が、少なくとも約5000Daの分子量を有する、請求項58に記載の前記方法。
- 前記化合物が、(i)NH及び/もしくはOH及び/もしくは他の可能性のある水素結合供与体部分の約5超の総数、(ii)O原子及び/もしくはN原子及び/もしくは他の可能性のある水素結合受容体の約10超の総数、ならびに/または(iii)約105超もしくは約10未満のMoriguchi分配係数を有する、請求項58に記載の前記方法。
- 前記化合物が、約100×10−6cm/s未満、または約10×10−6cm/s未満、または約1×10−6cm/s未満、または約0.1×10−6cm/s未満の透過係数Pappを有する、請求項58に記載の前記方法。
- 1つ以上の追加の生物活性剤を投与することをさらに含む、請求項1〜70のいずれか1項に記載の前記方法。
- 前記化合物及び前記1つ以上の追加の生物活性剤が、単一の薬学的組成物の一部として投与される、請求項71に記載の前記方法。
- 前記化合物及び前記1つ以上の追加の生物活性剤が、個別の薬学的組成物として投与される、請求項71に記載の前記方法。
- 前記個別の薬学的組成物が、順次に投与される、請求項73に記載の前記方法。
- 前記個別の薬学的組成物が、同時に投与される、請求項73に記載の前記方法。
- 前記追加の生物活性剤が、ビタミンD2(エルゴカルシフェロール)、ビタミンD3(コレカルシフェロール)、活性型ビタミンD(カルシトリオール)、及び活性型ビタミンD類似体(例えばドキセルカルシフェロール、パリカルシトール)から選択される、請求項71〜75のいずれか1項に記載の前記方法。
- 前記追加の生物活性剤が、リン酸塩結合剤である、請求項71〜75のいずれか1項に記載の前記方法。
- 前記リン酸塩結合剤が、セベラマー(例えば、Renvela(登録商標)(炭酸セベラマー)、Renagel(登録商標)(塩酸セベラマー))、炭酸ランタン(例えば、Fosrenol(登録商標))、炭酸カルシウム(例えば、Calcichew(登録商標)、Titralac(登録商標))、酢酸カルシウム(例えばPhosLo(登録商標)、Phosex(登録商標))、酢酸カルシウム/炭酸マグネシウム(例えば、Renepho(登録商標)、OsvaRen(登録商標))、MCI−196、クエン酸第二鉄(例えば、Zerenex(商標))、水酸化炭酸鉄マグネシウム(例えば、Fermagate(商標))、水酸化アルミニウム(例えば、Alucaps(登録商標)、Basaljel(登録商標))、APS1585、SBR−759、及びPA−21から成る群から選択される、請求項77に記載の前記方法。
- 前記追加の生物活性剤が、NaPi2b阻害薬である、請求項71〜75のいずれか1項に記載の前記方法。
- 前記追加の生物活性剤が、ナイアシンまたはニコチンアミドである、請求項71〜75のいずれか1項に記載の前記方法。
- 前記対象がCKDを有し、前記さらに活性な生物剤が、ACE阻害薬、アンチオゲンシンII受容体遮断薬、β遮断薬、カルシウムチャネル遮断薬、直接的レニン阻害薬、利尿薬、血管拡張薬、エリスロポエチン療法、鉄補充療法、終末糖化産物の阻害薬、ビタミンD、及びスタチンのうちの1つ以上から選択される、請求項71〜75のいずれか1項に記載の前記方法。
- 前記化合物または組成物が、経口投与される、請求項1〜81のいずれか1項に記載の前記方法。
- 前記化合物または組成物が、1日1回経口投与される、請求項82に記載の前記方法。
- リン酸塩取り込みの阻害薬のスクリーニングの方法であって、(a)腸細胞を培養することと、(b)前記培養された腸細胞を試験化合物と接触させることと、(c)(i)前記腸細胞の頂端表面におけるpH、(ii)前記腸細胞の細胞内pH、及び/または(iii)前記腸細胞によるリン酸塩取り込みを測定することと、(d)(c)(i)の前記pHが対照と比べて増加し、(c)(ii)の前記細胞内pHが対照と比べて減少し、かつ/または(c)(iii)のリン酸塩取り込みが対照と比べて減少する場合、前記試験化合物をリン酸塩取り込みの阻害薬として特定することと、を含む、前記方法。
- ステップ(a)が、腸細胞を単層培養することを含む、請求項84に記載の前記方法。
- ステップ(a)が、腸陰窩から前記細胞を単離し、エンテロイド(enteroid)を形成するのに十分な条件下で培養することを含む、請求項84に記載の前記方法。
- ステップ(a)が、単離した胚性幹細胞、内胚葉細胞、または多能性幹細胞を、オルガノイドを形成するのに十分な条件下で培養することを含む、請求項84に記載の前記方法。
- ステップ(a)が、腸切片(複数可)をUssingチャンバ内で培養することを含む、請求項84に記載の前記方法。
- ステップ(c)(i)が、前記細胞をpH感応性蛍光染料と接触させることと、前記染料の蛍光を測定することと、を含む、請求項84に記載の前記方法。
- ステップ(c)(ii)が、前記細胞を33P標識化リン酸イオンと接触させることと、前記標識化リン酸イオンの取り込みを測定することと、を含む、請求項84に記載の前記方法。
- (d)の前記増加及び/または減少が、統計的に有意である、請求項84に記載の前記方法。
- 前記試験化合物が、小腸内の重炭酸塩分泌を刺激し、かつ/または酸分泌を阻害することで知られるか、あるいはその疑いがある小分子またはペプチドである、請求項84に記載の前記方法。
- 前記試験化合物が、P2Y作動薬、アデノシンA2b受容体作動薬、グアニル酸シクラーゼC受容体作動薬、可溶性グアニル酸シクラーゼ作動薬、アデニル酸シクラーゼ受容体作動薬、イミダゾリン−1受容体作動薬、コリン作動薬、プロスタグランジンEP4受容体作動薬、ドパミンD1作動薬、メラトニン受容体作動薬、5HT4作動薬、心房性ナトリウム利尿ペプチド受容体作動薬、炭酸脱水酵素阻害薬、ホスホジエステラーゼ阻害薬、及び腺腫において下方制御される交換輸送体(DRAまたはSLC26A3)作動薬のうちの1つ以上から選択される、請求項92に記載の前記方法。
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