6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione - CAS号 82319-96-8

计算性质

辛醇/水分配系数(LogP)：

1.9
重原子数：

19
可旋转键数：

0
环数：

3.0
sp3杂化的碳原子比例：

0.38
拓扑面积：

67.4
氢给体数：

2
氢受体数：

3

上下游信息

下游产品

中文名称	英文名称	CAS号	化学式	分子量
——	6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione	1311264-93-3	C₁₄H₁₅BrN₂O₃	339.189
——	2,2-dimethyl-6-bromo-1'-(3-dimethylaminopropyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione	99600-04-1	C₁₈H₂₄BrN₃O₃	410.311
——	6-bromo-1′-(2-methoxyethyl)-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione	1430416-55-9	C₁₆H₁₉BrN₂O₄	383.242
——	6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione	1430416-52-6	C₁₅H₁₄BrF₃N₂O₃	407.187
——	6-bromo-2,2-dimethyl-2'-sulfanylidenespiro[3H-chromene-4,5'-imidazolidine]-4'-one	148794-98-3	C₁₃H₁₃BrN₂O₂S	341.228
——	6-Bromo-2,2-dimethyl-2'-ethylamino-2,3,3',4'-tetrahydro-spiro-[4H-1-benzopyran-4,4'-5'H-imidazol]-5'one	——	C₁₅H₁₈BrN₃O₂	352.231
——	6-bromo-1′,2,2-trimethyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one	1311264-94-4	C₁₄H₁₅BrN₂O₂S	355.255
——	6-bromo-1′-ethyl-2,2-dimethyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one	1430416-50-4	C₁₅H₁₇BrN₂O₂S	369.282
——	6-bromo-1′-(2-methoxyethyl)-2,2-dimethyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one	1430416-56-0	C₁₆H₁₉BrN₂O₃S	399.308
——	6-bromo-2,2-dimethyl-2′-thioxo-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazolidin]-5′-one	1430416-53-7	C₁₅H₁₄BrF₃N₂O₂S	423.254
——	(E)-N′-(6-bromo-2,2-dimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-2′-yl)-N,N-dimethylformimidamide	1430416-58-2	C₁₆H₁₉BrN₄O₂	379.256
——	2′-amino-6-bromo-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1212010-85-9	C₁₄H₁₆BrN₃O₂	338.204
——	6'-bromo-2',2'-dimethyl-2-methylsulfanylspiro[1H-imidazole-4,4'-3H-chromene]-5-one	148795-13-5	C₁₄H₁₅BrN₂O₂S	355.255
——	2′-amino-6-bromo-1′-ethyl-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-51-5	C₁₅H₁₈BrN₃O₂	352.231
——	6'-bromo-2',2'-dimethyl-2-propylsulfanylspiro[1H-imidazole-4,4'-3H-chromene]-5-one	——	C₁₆H₁₉BrN₂O₂S	383.309
——	1′-((1-acetylpiperidin-4-yl)methyl)-2′-amino-6-bromo-2,2-dimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-62-8	C₂₁H₂₇BrN₄O₃	463.374
——	2′-amino-6-bromo-1′-(2-methoxyethyl)-2,2-dimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-57-1	C₁₆H₂₀BrN₃O₃	382.257
——	2′-amino-6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-54-8	C₁₅H₁₅BrF₃N₃O₂	406.202
——	6-Bromo-2,2-Dimethyl-2'-ethoxy-2,3,3',4'-tetrahydro-spiro-[4H-1-benzopyran-4,4'-5'H-imidazol]-5'one	148582-63-2	C₁₅H₁₇BrN₂O₃	353.216
——	(E)-N′-(6-bromo-2,2-dimethyl-5′-oxo-1′-(piperidin-4-ylmethyl)-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-2′-yl)-N,N-dimethylformimidamide	1430416-60-6	C₂₂H₃₀BrN₅O₂	476.416
——	(E)-N′-(1′-((1-acetylpiperidin-4-yl)methyl)-6-bromo-2,2-dimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-2′-yl)-N,N-dimethylformimidamide	1430416-61-7	C₂₄H₃₂BrN₅O₃	518.454
——	2′-amino-6-hydroxy-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-44-6	C₁₄H₁₇N₃O₃	275.307
——	2′-amino-6-isobutoxy-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-35-5	C₁₈H₂₅N₃O₃	331.415
——	2′-amino-6-cyclohexyl-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311261-36-5	C₂₀H₂₇N₃O₂	341.453
——	2′-amino-6-(3-fluorophenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-63-5	C₂₀H₂₀FN₃O₂	353.396
——	2′,6-diamino-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-45-7	C₁₄H₁₈N₄O₂	274.323
——	2′-amino-6-(5-chloropyridin-3-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311261-94-5	C₂₀H₂₁N₃O₂	335.406
——	2′-amino-6-(4-methoxyphenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311262-32-4	C₂₁H₂₃N₃O₃	365.432
——	2'-amino-1',2,2-trimethyl-6-(3-methylbut-1-ynyl)spiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-52-5	C₁₉H₂₃N₃O₂	325.411
——	2'-amino-6-(5-bromopyridin-3-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-34-3	C₁₉H₁₉BrN₄O₂	415.289
——	2′-amino-1′,2,2-trimethyl-6-(pyridin-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311263-72-5	C₁₉H₂₀N₄O₂	336.393
——	2′-amino-1′,2,2-trimethyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-68-0	C₂₁H₂₀F₃N₃O₂	403.404
——	2′-amino-6-(3-chloro-5-fluorophenyl)-1′,2,2-trimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-58-8	C₂₀H₁₉ClFN₃O₂	387.841
——	2'-amino-6-(3-cyclopropyl-5-fluorophenyl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-27-4	C₂₃H₂₄FN₃O₂	393.461
——	2′-amino-1′,2,2-trimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311261-19-4	C₁₈H₁₉N₅O₂	337.381
——	3-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile	1231722-95-4	C₂₁H₂₀N₄O₂	360.415
——	2′-amino-6-(3-chlorophenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-59-9	C₂₀H₂₀ClN₃O₂	369.851
——	2′-amino-1′,2,2-trimethyl-6-(pyridin-4-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-38-8	C₁₉H₂₀N₄O₂	336.393
——	2′-amino-6-(3,5-dichlorophenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-52-2	C₂₀H₁₉Cl₂N₃O₂	404.296
——	3-(2'-amino-1',2,2-trimethyl-5'-oxo-1',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-fluorobenzonitrile	1311261-25-2	C₂₁H₁₉FN₄O₂	378.406
——	3-(2'-amino-1',2,2-trimethyl-5'-oxo-1',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-cyclopropylbenzonitrile	1311261-29-6	C₂₄H₂₄N₄O₂	400.48
——	2′-amino-6-(5-chloropyridin-3-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-51-1	C₁₉H₁₉ClN₄O₂	370.838
——	(R)-2′-amino-6-(5-chloropyridin-3-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-78-2	C₁₉H₁₉ClN₄O₂	370.838
——	2′-amino-6-(3-fluoro-5-methoxyphenyl )-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-65-7	C₂₁H₂₂FN₃O₃	383.422
——	2′-amino-1′,2,2-trimethyl-6-(5-(trifluoromethyl)pyridin-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-53-3	C₂₀H₁₉F₃N₄O₂	404.392
——	2′-amino-6-(3-methoxyphenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-66-8	C₂₁H₂₃N₃O₃	365.432
——	2′-amino-1′,2,2-trimethyl-6-(pyridin-2-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-37-7	C₁₉H₂₀N₄O₂	336.393
——	2′-amino-6-(3-ethoxyphenyl)-1′,2,2-trimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1311262-06-2	C₂₂H₂₅N₃O₃	379.459
——	2′-amino-6-(3-isopropoxyphenyl)-1′,2,2-trimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1311262-35-7	C₂₃H₂₇N₃O₃	393.486
——	2′-amino-1′,2,2-trimethyl-6-(3-(methylthio)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311263-06-5	C₂₁H₂₃N₃O₂S	381.499
——	2′-amino-6-(2-methoxyphenyl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311262-31-3	C₂₁H₂₃N₃O₃	365.432
——	2'-amino-6-(3-chloro-5-ethynylphenyl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-15-0	C₂₂H₂₀ClN₃O₂	393.873
——	2′-amino-6-(5-fluoropyridin-3-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-60-2	C₁₉H₁₉FN₄O₂	354.384
——	2'-amino-6-(4-chloropyridin-2-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-12-7	C₁₉H₁₉ClN₄O₂	370.838
——	2'-amino-6-(3-chloro-5-((trimethylsilyl)ethynyl)phenyl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311265-12-9	C₂₅H₂₈ClN₃O₂Si	466.055
——	2-(2'-amino-1',2,2-trimethyl-5'-oxo-1',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)isonicotinonitrile	1311261-10-5	C₂₀H₁₉N₅O₂	361.403
——	2′-amino-6-(3-(difluoromethoxy)phenyl )-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311261-35-4	C₂₁H₂₁F₂N₃O₃	401.413
——	2'-amino-6-(4-methoxypyridin-2-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-11-6	C₂₀H₂₂N₄O₃	366.42
——	1′-((1-acetylpiperidin-4-yl)methyl)-2′-amino-6-(3-chlorophenyl)-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311263-80-5	C₂₇H₃₁ClN₄O₃	495.021
——	2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1311265-24-3	C₂₀H₂₈BN₃O₄	385.271
——	2'-amino-6-(5-ethynylpyridin-3-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-13-8	C₂₁H₂₀N₄O₂	360.415
——	2′-amino-6-(3-chlorophenyl)-1′-(2-methoxyethyl)-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-74-8	C₂₂H₂₄ClN₃O₃	413.904
——	N-(2′-amino-1′,2,2-trimethyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-5-methylfuran-2-carboxamide	1430416-39-9	C₂₀H₂₂N₄O₄	382.419
——	2′-amino-6-(5-chloro-2-fluorophenyl)-1′,2,2-trimethylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-61-3	C₂₀H₁₉ClFN₃O₂	387.841
——	2'-amino-6-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311261-53-6	C₂₀H₂₁ClN₄O₃	400.865
——	2′-amino-1′,2,2-trimethyl-6-(5-(prop-1-ynyl)pyridin-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311261-14-9	C₂₂H₂₂N₄O₂	374.442
——	2′-amino-6-(3-chlorophenyl)-1′-ethyl-2,2-dimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-73-7	C₂₁H₂₂ClN₃O₂	383.878
——	2′-amino-6-(2-fluoro-5-methoxyphenyl )-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311260-56-6	C₂₁H₂₂FN₃O₃	383.422
——	2′-amino-6-(isothiazol-5-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311263-07-6	C₁₇H₁₈N₄O₂S	342.422
——	2′-amino-1′,2,2-trimethyl-6-(piperidin-1-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1430416-36-6	C₁₉H₂₆N₄O₂	342.441
——	2′-amino-6-(3-chlorophenyl)-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311262-62-0	C₂₁H₁₉ClF₃N₃O₂	437.849
——	2′-amino-6-(2-fluoropyridin-3-yl)-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one	1311263-82-7	C₁₉H₁₉FN₄O₂	354.384
——	2'-amino-6-(6-chloroimidazo[1,2-a]pyridin-8-yl)-1',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(1'H)-one	1311260-89-5	C₂₁H₂₀ClN₅O₂	409.875

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反应信息

作为反应物：

描述：

6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione 在四(三苯基膦)钯劳森试剂、叔丁基过氧化氢、 ammonium hydroxide 、 sodium hydride 、 sodium carbonate 作用下，以 1,4-二氧六环、甲醇、 N,N-二甲基甲酰胺、甲苯、 mineral oil 为溶剂，反应 17.0h，生成 2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one

参考文献：

名称：

[EN] S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
[FR] SPIRO[CHROMANE-4,4'-IMIDAZOL]ONES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE

摘要：

这项发明提供了Formula I和Formula II的新型螺环色苷化合物，可以抑制APP的β-分泌酶裂解，并可用作治疗神经退行性疾病的治疗剂。

公开号：

WO2011072064A1
作为产物：

描述：

2-羟基-5-溴苯乙酮在四氢吡咯作用下，以甲苯为溶剂，反应 91.0h，生成 6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione

参考文献：

名称：

[EN] S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
[FR] SPIRO[CHROMANE-4,4'-IMIDAZOL]ONES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE

摘要：

这项发明提供了Formula I和Formula II的新型螺环色苷化合物，可以抑制APP的β-分泌酶裂解，并可用作治疗神经退行性疾病的治疗剂。

公开号：

WO2011072064A1

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文献信息

Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers

作者：Robert C. Gadwood、Bharat V. Kamdar、Loretta A. Cipkus Dubray、Mark L. Wolfe、Michael P. Smith、William Watt、Stephen A. Mizsak、Vincent E. Groppi

DOI：10.1021/jm00062a022

日期：1993.5

A series of novel spirocyclic benzopyran imidazolones were synthesized as rigid analogues of cromakalim. These compounds cause a dose-dependent membrane hyperpolarization of A10 rat aorta cells. This hyperpolarization was blocked by pretreatment with glyburide, indicating that the spirocyclic benzopyran imidazolones were acting by increasing the open probability of ATP-sensitive potassium channels

合成了一系列新颖的螺环苯并吡喃咪唑酮，作为克罗马卡林的刚性类似物。这些化合物引起A10大鼠主动脉细胞的剂量依赖性膜超极化。这种超极化被格列本脲预处理所阻断，表明螺环苯并吡喃咪唑酮通过增加A10细胞中ATP敏感性钾通道的开放可能性而起作用。代表性化合物还显示出在血压正常大鼠中作为降压药的有效体内活性。所描述的许多化合物在体外和体内均比克罗马卡林有效得多，其中最有效的化合物之一是2,3-二氢-2,2-二甲基-6-硝基-2'-（丙基氨基）螺[ 4H-1-苯并吡喃-4,4'-[4H]咪唑] -5'（1'H）-一（5r）。结论是N1' 咪唑啉酮的氮是克罗马卡林的羰基氧的有效替代物。刚性螺环稠合使该氮相对于苯并吡喃环保持最佳方向。
Synthesis and Antiarrhythmic Activity of 2,2-Dialkyl-1'-(N-substituted aminoalkyl)-spiro-(chroman-4,4'-imidazolidine)-2',5'-diones.

作者：Masayuki MATSUKURA、Yoshiharu DAIKU、Kouichirou UEDA、Satoru TANAKA、Toshiji IGARASHI、Norio MINAMI

DOI：10.1248/cpb.40.1823

日期：——

A novel series of 2, 2-dialkyl-1'-(N-substituted aminoalkyl)-spiro-[chroman-4, 4'-imidazolidine]-2', 5'-diones was synthesized and evaluated for antiarrhythmic activity in chloroform- or/and aconitine-induced ventricular arrhythmia in mice. Among these compounds, (-)-6-chloro-2, 2-dimethyl-1'-[3-(4-hydroxypiperidino)propyl]-spiro-[chroman-4, 4'-imidazolidine]-2', 5'-dione was found to be more effective than reference agents and was selected for further development.

合成了一系列新型的2, 2-二烷基-1'-(N-取代氨基烷基)-螺-[色满-4, 4'-咪唑烷]-2', 5'-二酮化合物，并评估了其在氯仿或/和乌头碱诱导的小鼠心室心律失常中的抗心律失常活性。在这些化合物中，(-)-6-氯-2, 2-二甲基-1'-[3-(4-羟基哌啶基)丙基]-螺-[色满-4, 4'-咪唑烷]-2', 5'-二酮被发现比参考药物更有效，并被选作进一步开发。
Inhibitors Of Beta-Secretase

申请人：Dillard Lawrence W.

公开号：US20110218192A1

公开（公告）日：2011-09-08

The present invention is directed to a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof. Pharmaceutical composition comprising a compound represented by Structural Formula (I) and method of use of these compound for inhibiting BACE activity in a subject in need of such treatment are also described.

本发明涉及以下结构式所表示的化合物或其药学上可接受的盐。还描述了包含由结构式（I）所表示的化合物的药物组合物和使用这些化合物抑制需要此类治疗的受体中的BACE活性的方法。
INHIBITORS OF BETA-SECRETASE

申请人：Dillard Lawrence W.

公开号：US20130317014A1

公开（公告）日：2013-11-28

The present invention is directed to a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof. Pharmaceutical composition comprising a compound represented by Structural Formula (I) and method of use of these compound for inhibiting BACE activity in a subject in need of such treatment are also described.

本发明涉及以下结构式所代表的化合物：或其药学上可接受的盐。还描述了包括结构式（I）所代表的化合物的药物组合物以及使用这些化合物抑制需要此类治疗的受体中的BACE活性的方法。
Spirocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid β in a Higher Species

作者：Kevin W. Hunt、Adam W. Cook、Ryan J. Watts、Christopher T. Clark、Guy Vigers、Darin Smith、Andrew T. Metcalf、Indrani W. Gunawardana、Michael Burkard、April A. Cox、Mary K. Geck Do、Darrin Dutcher、Allen A. Thomas、Sumeet Rana、Nicholas C. Kallan、Robert K. DeLisle、James P. Rizzi、Kelly Regal、Douglas Sammond、Robert Groneberg、Michael Siu、Hans Purkey、Joseph P. Lyssikatos、Allison Marlow、Xingrong Liu、Tony P. Tang

DOI：10.1021/jm4002154

日期：2013.4.25

A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (A beta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. A beta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A beta in vivo, despite efflux. Starting with spirocycle la, we explore structure activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A beta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A beta in rodents and in monkey.

6-bromo-2,2-dimethylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione | 82319-96-8

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