LSP-11128 | 99427-76-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: LSP-11128
• 英文别名: (3S)-3-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl]ethanoic acid；(3S)-2-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl]ethanoic acid；(2S)-2-amino-4-[carboxymethyl(hydroxy)phosphoryl]butanoic acid
• CAS: 99427-76-6
• 化学式: C₆H₁₂NO₆P
• 分子量: 225.138
• InChiKey: QNZCMPXFRMGKRU-BYPYZUCNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  138
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl (3S)-2-[((3-(N-benzyloxycarbonyl)amino-3-(methoxycarbonyl)propyl)(hydroxy)phosphinyl)]ethanoate 在 盐酸 、 水 作用下， 以6.6 mg的产率得到LSP-11128
  参考文献：
  名称：

  A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

  摘要：

  (R)-PCEP (3-amino-3-carboxypropy1-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC50 of 1.0 +/- 0.2 mu M at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC50 of 43 +/- 16 mu M and is thus significantly more potent than L-AP4 (EC50 of 249 +/- 106 mu M).

  DOI：

  10.1021/jm901523t

文献信息

• Hypophosphorous Acid Derivatives and their Therapeutical Applications
  申请人：Acher Francine

  公开号：US20090170813A1

  公开（公告）日：2009-07-02

  Hypophosphorous acid derivatives having Formula (I) wherein .M is a [C(R3,R4)]n1-C(E,COOR1,N(H,Z)) group, or an optionally substituted Ar—CH(COOR1,N(H,Z)) group, or an a, β, or a β, g-cyclic amino acid; .R 1 is H or R, R being an hydroxy or a carboxy protecting group; .Z is H or an amino protecting group R′, benzyl oxycarbonyl, benzyl or benzyl substituted; .E is H or a C1-C3 alkyl, aryl, an hydrophobic group; .R 2 is selected in the group comprising: D-CH(R 6 )—C—(R 7 ,R 8 ), (R 11 ,R 12 )CH—C(R 9 ,R 10 ), D-CH(OH), D-[C(R 13 ,R 14 )] n3 —, C[(R 15 ,R 16 ,R 17 )] n4 , D-CH 2 , (R 18 )CH═C(R 19 ), D-(M 1 ) n6 —CO, Formula (II), PO(OH) 2 —CH 2 or (PO(OH) 2 —CH 2 ), (COOH—CH 2 )—CH 2 , with -D=H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 COOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 ) n2 -alkyl, (COOH,NH 2 )—(CH 2 ) u1 -cyclopropyl-(CH 2 ) u2 —, CO—NH-alkyl, Ar, (CH 2 ) n2 —Ar, CO—NH—Ar; —R 3 to R 19 being H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 COOR, C 1 -C 3 alkyl, cycloalkyl, (CH 2 )n1-alkyl, aryl, (CH 2 )n1-aryl, halogen, CF 3 , SO 3 H, (CH 2 ) x PO 3 H 2 , with x=0, 1 or 2, B(OH) 2 , Formula (III), NO 2 , SO 2 NH 2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; -M 1 is an alkylene or arylene group; -n1=1, 2 or 3, n2=1, 2 or 3, n3=0, 1, 2 or 3 and n4=1, 2 or 3, n5=1, 2 or 3, n6=0 or 1, u1 and u2, identical or different=0, 1 or 2, with the proviso that Formula (I) does not represent the racemic (3R,S) and the enantiomeric form (3R) of 3 amino,3-carboxy-propyl-2′-carboxy-ethylphosphinic acid; 3 amino,3-carboxy-propyl-4′carboxy,2′carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl-2′carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl-3′amino, 3′carboxy-propylylphosphinic acid; and 3 amino,3-carboxypropyl-7′amino-2′, 7′-dicarboxyheptylphosphinic acid, said hypophosphorous acid derivatives being diasteroisomers or enantiomers. Application as drugs.

  含有Formula (I)的次磷酸衍生物，其中.M是[C(R3,R4)]n1-C(E,COOR1,N(H,Z))基团，或者是一个可选择取代的Ar—CH(COOR1,N(H,Z))基团，或者是α，β或αβ，γ-环氨基酸；.R1是H或R，R是一个羟基或羧基保护基团；.Z是H或氨基保护基团R′，苄氧羰基，苄基或苄基取代；.E是H或C1-C3烷基，芳基，疏水基团；.R2是从以下群体中选择的：D-CH(R6)—C—(R7,R8)，(R11,R12)CH—C(R9,R10)，D-CH(OH)，D-[C(R13,R14)]n3—，C[(R15,R16,R17)]n4，D-CH2，(R18)CH═C(R19)，D-(M1)n6—CO，Formula (II)，PO(OH)2—CH2或(PO(OH)2—CH2)，(COOH—CH2)—CH2，其中-D=H，OH，OR，(CH2)n2OH，(CH2)n1OR，COOH，COOR，(CH2)n2COOH，(CH2)n1COOR，SR，S(OR)，SO2R，NO2，杂环芳基，C1-C3烷基，环烷基，杂环烷基，(CH2)n2-烷基，(COOH,NH2)—(CH2)u1-环丙基-(CH2)u2—，CO—NH-烷基，Ar，(CH2)n2—Ar，CO—NH—Ar；—R3到R19为H，OH，OR，(CH2)n2OH，(CH2)n1OR，COOH，COOR，(CH2)n2COOH，(CH2)n1COOR，C1-C3烷基，环烷基，(CH2)n1-烷基，芳基，(CH2)n1-芳基，卤素，CF3，SO3H，(CH2)xPO3H2，其中x=0，1或2，B(OH)2，Formula (III)，NO2，SO2NH2，SO2NHR；SR，S(O)R，SO2R，苄基；-M1是一个烷基或芳基基团；-n1=1，2或3，n2=1，2或3，n3=0，1，2或3，n4=1，2或3，n5=1，2或3，n6=0或1，u1和u2，相同或不同=0，1或2，但Formula (I)不代表3-氨基，3-羧基-丙基-2′-羧基-乙磷酸的消旋体(3R,S)和对映体形式(3R)；3-氨基，3-羧基-丙基-4′羧基，2′羧基-丁酰磷酸；3-氨基，3-羧基-丙基-2′羧基-丁酰磷酸；3-氨基，3-羧基-丙基-3′氨基，3′羧基-丙基磷酸；和3-氨基，3-羧基丙基-7′氨基-2′，7′-二羧基庚基磷酸，所述的次磷酸衍生物为二对映异构体或对映体。用作药物的应用。
• HYPOPHOSPHOROUS ACID DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
  申请人：CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)

  公开号：EP1937699A2

  公开（公告）日：2008-07-02
• [EN] HYPOPHOSPHOROUS ACID DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS<br/>[FR] DERIVES ACIDES HYPOPHOSPHORES ET APPLICATIONS THERAPEUTIQUES
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2007052169A2

  公开（公告）日：2007-05-10

  [EN] Hypophosphorous acid derivatives having Formula (I) wherein . M is a [C(R3,R4)]n1 - C(E,COOR1, N(H, Z)) group, or an optionally substituted Ar-CH(COOR1, N(H, Z)) group, or an a, ß, or a ß, g-cyclic aminoacid; . R₁ is H or R, R being an hydroxy or a carboxy protecting group; . Z is H or an amino protecting group R', benzyl oxycarbonyl, benzyl or benzyl substituted; . E is H or a C1-C3 alkyl, aryl, an hydrophobic group; . R₂ is selected in the group comprising: D-CH(R₆)- C-(R₇, R₈), (R₁₁,R₁₂)CH- C(R₉, R₁₀), D - CH(OH), D- [C(R₁₃, R₁₄)]_n3 -, C[(R₁₅, R₁₆, R₁₇)]_n4, D-CH₂, (R₁₈)CH = C(R₁₉), D-(M₁)_n6-CO, Formula (II), PO(OH)₂-CH₂ or (PO(OH)₂-CH₂), (COOH-CH₂)-CH₂, with - D = H, OH, OR, (CH₂)_n2OH, (CH₂)_n1OR, COOH, COOR, (CH₂)_n2COOH, (CH₂)_n1COOR, SR, S(OR), SO₂R, NO₂, heteroaryl, C₁-C₃ alkyl, cycloalkyl, heterocycloalkyl, (CH₂)_n2-alkyl, (COOH, NH₂)-(CH₂)_u1-cyclopropyl-(CH₂)_u2-, CO-NH-alkyl, Ar, (CH₂)_n2-Ar, CO-NH-Ar; - R₃ to R₁₉ being H, OH, OR, (CH₂)_n2OH, (CH₂)_n1OR, COOH, COOR, (CH₂)_n2COOH, (CH₂)_n1COOR, C₁-C₃ alkyl, cycloalkyl, (CH₂)n1-alkyl, aryl, (CH₂)n1-aryl, halogen, CF₃, SO₃H, (CH₂)_x PO₃H₂, with x = 0, 1 or 2, B(OH)₂ , Formula (III), NO₂ , SO₂NH₂ , SO₂NHR; SR, S(O)R, SO₂R, benzyl; - M₁ is an alkylene or arylene group; - n1= 1, 2 or 3, n2= 1, 2 or 3, n3= 0, 1, 2 or 3 and n4= 1, 2 or 3, n5= 1,2 or 3, n6= 0 or 1, u1 and u2, identical or different = 0,1 or 2, with the proviso that Formula (I) does not represent the racemic (3R, S) and the enantiomeric form (3R) of 3 amino,3-carboxy-propyl-2'-carboxy-ethylphosphinic acid; 3 amino,3-carboxy-propyl- 4'carboxy,2'carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 2'carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 3'amino, 3'carboxy-propylylphosphinic acid; and 3 amino,3-carboxypropyl -7'amino-2', 7'-dicarboxyheptylphosphinic acid, said hypophosphorous acid derivatives being diasteroisomers or enantiomers. Application as drugs.
  [FR] Cette invention concerne des dérivés acides hypophosphorés représentés par la formule (I). Dans cette formule, M est un groupe [C(R3,R4)]n1 - C(E,COOR1, N(H, Z)), ou un groupe Ar-CH(COOR1, N(H, Z)) éventuellement substitué, ou un acide aminé a, ß, ou g-cyclique; . R₁ est H ou R, R étant un groupe protecteur hydroxy ou carboxy; . Z est H ou un groupe amino protecteur R', benzyl oxycarbonyl, benzyle ou substitué benzyle; E est H ou un C1-C3 alkyle, aryle, un groupe hydrophobe; . R2 est pris dan le groupe comprenant: D-CH(R₆)- C-(R₇, R₈), (R₁₁,R₁₂)CH- C(R₉, R₁₀), D - CH(OH), D- [C(R₁₃, R₁₄)]_n3 -, C[(R₁₅, R₁₆, R₁₇)]_n4, D-CH₂, (R₁₈)CH = C(R₁₉), D-(M₁)_n6-CO, PO(OH)2-CH₂ ou (PO(OH)₂-CH₂), (COOH-CH₂)-CH₂, avec - D = H, OH, OR, (CH₂)_n2OH, (CH₂)_n1OR, COOH, COOR, (CH₂)_n2COOH, (CH₂)_n1COOR, SR, S(OR), SO₂R, NO₂, hétéroaryle, C1-C3 alkyle, cycloalkyle, hétérocycloalkyle, (CH₂)_n2-alkyle, (COOH, NH₂)-(CH₂)_u1-cyclopropyl-(CH₂)_u2-, CO-NH-alkyle, Ar, (CH₂)_n2-Ar, CO-NH-Ar; - R₃ à R₁₉ étant H, OH, OR, (CH₂)_n2OH, (CH₂)_n1OR, COOH, COOR, (CH₂)_n2COOH, (CH₂)_n1COOR, C₁-C₃ alkyle, cycloalkyle, (CH₂)n1-alkyle, aryle, (CH₂)n1-aryle, halogène, CF₃, SO₃H, (CH₂)_x PO₃H₂, avec x = 0, 1 ou 2, B(OH)₂,, NO₂, SO₂NH₂, SO₂NHR; SR, S(O)R, SO₂R, benzyle; - M₁ est un groupe alkylène ou arylène; - n1= 1, 2 ou 3, n2= 1, 2 ou 3, n3= 0, 1, 2 ou 3 et n4= 1, 2 ou 3, n5= 1,2 ou 3, n6= 0 or 1, u1 and u2, identiques ou différents = 0,1 ou 2, à condition quela formule (I) ne représenter pas la forme racémique (3R, S) ni la forme énantiomère (3R) de 3 amino,3-carboxy-propyl-2'-carboxy-éthylphosphinique acide; 3 amino,3-carboxy-propyl- 4'carboxy,2'carboxy-butanoylphosphinique acide; 3 amino,3-carboxy-propyl- 2'carboxy-butanoylphosphinique acide; 3 amino,3-carboxy-propyl- 3'amino, 3'carboxy-propylylphosphinique acide; and 3 amino,3-carboxypropyl -7'amino-2', 7'-dicarboxyheptylphosphinique acide, lesdits dérivées acides hypophosphorés étant des diastero-isoméres ou des énantiomères. Cette invention concerne également l'application de ces dérivés en tant que médicaments.
• A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists
  作者：Chelliah Selvam、Nadia Oueslati、Isabelle A. Lemasson、Isabelle Brabet、Delphine Rigault、Tiphanie Courtiol、Sara Cesarini、Nicolas Triballeau、Hugues-Olivier Bertrand、Cyril Goudet、Jean-Philippe Pin、Francine C. Acher

  DOI：10.1021/jm901523t

  日期：2010.4.8

  (R)-PCEP (3-amino-3-carboxypropy1-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC50 of 1.0 +/- 0.2 mu M at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC50 of 43 +/- 16 mu M and is thus significantly more potent than L-AP4 (EC50 of 249 +/- 106 mu M).