3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价（英文）
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摘要
作者基于课题组先前得到的具有较强α7烟碱型乙酰胆碱受体I型正向变构调节剂活性的先导化合物2,设计并合成了一系列的6位取代的3H-喹唑啉-4-酮化合物(3a-3d),所有目标化合物均通过对表达有人源α7乙酰胆碱受体的非洲爪蟾卵使用双电极电压钳技术来进行活性评价。然而,在100μM的乙酰胆碱作用下,所有化合物均没有显示出比先导化合物2更高的活性。由此证明噻唑[4,5-d]并嘧啶-7(6H)-酮母核是发挥正向变构调节活性的必需基团,是对先导化合物2的构效关系的补充。
A series of new 6-substituted 3 H-quinazolin-4-ones(3 a-3 d) were designed, synthesized and evaluated as the type I positive allosteric modulators(PAMs) of human α7 n ACh R expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine(100 μM). The structure-activity relationship(SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6 H)-one was the key biological skeleton.
A series of new 6-substituted 3 H-quinazolin-4-ones(3 a-3 d) were designed, synthesized and evaluated as the type I positive allosteric modulators(PAMs) of human α7 n ACh R expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine(100 μM). The structure-activity relationship(SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6 H)-one was the key biological skeleton.
引文
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[2](a)Seguela,P.;Wadiche,J.;Dineley-Miller,K.;Dani,J.A.;Patrick,J.W.Molecular cloning,functional properties,and distribution of rat brain alpha 7:A nicotinic cation channel highly permeable to calcium.J.Neurosci.1993,13,596-604.(b)Gotti,C.;Clementi,F.;Fornari,A.;Gaimarri,A.;Guiducci,S.;Manfredi,I.;Moretti,M.;Pedrazzi,P.;Pucci,L.;Zoli,M.Structural and functional diversity of native brain neuronal nicotinic receptors.Biochem.Pharmacol.2009,78,703-711.
[3](a)Xie,X.;Zhang,G.;Zhang,L.Advances onα7 n ACh Ras targets for drug development.Chin.J.Med.Chem.2015,25,313?323.(b)Hauser,T.A.;Kucinski,A.;Jordan,K.G.;Gatto,G.J.;Wersinger,S.R.;Hesse,R.A.;Stachowiak,E.K.;Stachowiak,M.K.;Papke,R.L.;Lippiello,P.M.;Bencherif,M.TC-5619:An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia.Biochem.Pharmacol.2013,355,32?37.(c)Wishka,D.G.;Walker,D.P.;Yates,K.M.;Reitz,S.C.;Jia,S.;Myers,J.K.;Olson,K.L.;Jacobsen,E.J.;Wolfe,M.L.;Groppi,V.E.;Hanchar,A.J.;Thornburgh,B.A.;Cortes-Burgos,L.A.;Wong,E.H.F.;Staton,B.A.;Raub,T.J.;Higdon,N.R.;Wall,T.M.;Hurst,R.S.;Walters,R.R.;Hoffmann,W.E.;Hajos,M.;Franklin,S.;Carey,G.;Gold,L.H.;Cook,K.K.;Sands,S.B.;Zhao,S.X.;Soglia,J.R.;Kalgutkar,A.S.;Arneric,S.P.;Rogers,B.N.Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide,An agonist of theα7 nicotinic acetylcholine receptor,for the potential treatment of cognitive deficits in schizophrenia:Synthesis and structure-activity relationship.J.Med.Chem.2006,49,4425?4436.
[4]Preskorn,S.H.;Gawryl,M.;Dgetluck,N.Normalizing effects of EVP-6124,an alpha-7 nicotinic partial agonist,on event-related potentials and cognition:a proof of concept,randomized trial in patients with schizophrenia.J.Psychiatr.Pract.2014,20,12?24.
[5](a)Williams,D.K.;Wang,J.;Papke,R.L.Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics:Advantages and limitations.Biochem.Pharmacol.2011,82,915-930.(b)Pandya,A.A.;Yakel,J.L.Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies.Biochem.Pharmacol.2013,86,1054-1062.
[6](a)Faghih,R.;Gopalakrishnan,M.;Briggs,C.A.Allosteric modulators of theα7 nicotinic acetylcholine receptor.J.Med.Chem.2008,51,701-712.(b)Gr?nlien,J.H.;Hakerud,M.;Ween,H.;Thorin-Hagene,K.;Briggs,C.A.;Gopalakrishnan,M.;Malysz,J.Distinct profiles ofα7 n ACh R positive allosteric modulation revealed by structurally diverse chemotypes.Mol.Pharmacol.2007,72,715-724.(c)Potasiewicz,A.;Ho?uj,M.;Kos,T.;Popik,P.;Arias,H.R.;Nikiforuk,A.3-Furan-2-yl-N-p-tolyl-acrylamide,a positive allosteric modulator of the a7 nicotinic receptor,reverses schizophrenia-like cognitive and social deficits in rats.Neuropharmacol.2017,113(Part A),188-197.
[7]Guerra-álvarez,M.;Moreno-Ortega,A.J.;Navarro,E.;Fernández-Morales,J.C.;Egea,J.;Lo?pez,M.G.;Cano-Abad,M.F.Positive allosteric modulation of alpha-7nicotinic receptors promotes cell death by inducing Ca2+release from the endoplasmic reticulum.J.Neurochem.2015,133,309-319.
[8](a)Gotti,C.;Clementi,F.;Zoli,M.Brain nicotinic acetylcholine receptors:Native subtypes and their relevance.Trends Pharmacol.Sci.2006,27,482?491.(b)Sharma,G.;Vijayaraghavan,S.Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores.Proc.Natl.Acad.Sci.USA.2001,98,4148?4153.(c)Yakel J.L.Nicotinic ACh receptors in the hippocampal circuit;functional expression and role in synaptic plasticity.J.Physiol.2014,592,4147?4153.
[9](a)Krause,R.M.;Buisson,B.;Bertrand,S.;Corringer,P.J.;Galzi,J.L.;Changeux,J.P.;Bertrand,D.Ivermectin:Apositive allosteric effector of theα7 neuronal nicotinic acetylcholine receptor.Mol.Pharmacol.1998,53,283?294.(b)Lopes,C.;Pereira,E.F.;Wu,H.Q.;Purushottamachar,P.;Njar,V.;Schwarcz,R.;Albuquerque,E.X.Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid atα7 nicotinic receptors.J.Pharmacol.Exp.Ther.2007,322,48?58.(c)Zwart,R.;Filippi,G.D.;Broad,L.M.;Mc Phie,G.I.;Pearson,K.H.;Baldwinson,T.;Sher,E.5-Hydroxyindole potentiates humanα7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices.Neuropharmacology.2002,43,374?384.(d)Gr?nlien,J.H.;H?kerud,M.;Ween,H.;Thorin-Hagene,K.;Briggs,C.A.;Gopalakrishnan,M.;Malysz,J.Distinct profiles ofα7 n ACh R positive allosteric modulation revealed by structurally diverse chemotypes.Mol.Pharmacol.2007,72,715?724.(e)Ng,H.J.;Whittemore,E.R.;Tran,M.B.;Hogenkamp,D.J.;Broide,R.S.;Johnstone,T.B.;Zheng,L.;Stevens,K.E.;Gee,K.W.Nootropicα7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.Proc.Natl.Acad.Sci.USA.2007,104,8059?8064.(f)Timmermann,D.B.;Gr?nlien,J.H.;Kohlhaas,K.L.;Nielsen,E.?.;Dam,E.;J?rgensen,T.D.;Ahring,P.K.;Peters,D.;Holst,D.;Chrsitensen,J.K.;Malysz,J.;Briggs,C.A.;Gopalakrishnan,M.;Olsen,G.M.An allosteric modulator of theα7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.J.Pharmacol.Exp.Ther.2007,323,294?307.(g)Dunlop,J.;Lock,T.;Jow,B.;Sitzia,F.;Grauer,S.;Jow,F.;Kramer,A.;Bowlby,M.R.;Randall,A.;Kowal,D.;Gilbert,A.;Comery,T.A.;La Rocque,J.;Soloveva,V.;Brown,J.;Roncarati,R.Old and new pharmacology:Positive allosteric modulation of theα7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C)receptor antagonist SB-206553(3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']dipyrrole-1(2H)-carboxamide).J.Pharmacol.Exp.Ther.2009,328,766?776.(h)Broad,L.M.;Zwart,R.;Pearson,K.H.;Lee,M.;Wallace,L.;Mc Phie,G.I.;Emkey,R.;Hollinshead,S.P.;Dell,C.P.;Baker,S.R.;Sher,E.Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators.J.Pharmacol.Exp.Ther.2006,318,1108?1117.
[10](a)Huang,X.;Jiao,W.;Sun,Q.;Wang,K.Pharmacokinetic characterization of a novelα7 nicotinic acetylcholine receptor(n ACh R)positive allosteric modulator LD486 in rat plasma using a validated LC-MS/MS assay.J.Chin.Pharm.Sci.2016,25,517-525.(b)Wang,K.;Sun,Q.;Jiao,W.;Tang,J.Preparation of thiazolopyrimidinone compound and their medical use.Faming Zhuanli Shenqing.2017,CN 106279211 A 20170104(Patent in Chinese).
[11]Li,Y.H.;Sun,L.L.;Yang.T.Y.;Jiao,W.X.;Tang,J.S.;Huang,X.M.;Huang,Z.Z.;Meng,Y.;Luo,L.C.;Wang,X.T.;Bian,X.L.;Zhang,F.;Sun,Q.;Wang,K.W.Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice.J.Med.Chem.2018,DOI:10.1021/acs.jmedchem.7b01492.
[12]De Lucca,G.V.;Shi,Q.;Liu,Q.Small Molecule reversible inhibitors of Bruton's tyrosine kinase(BTK):Structure-activity relationships leading to the identification of 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide(BMS-935177).J.Med.Chem.2016,59,7915-7935.
[13]Zhang,H.;Cai,Q.;Ma,D.Amino acid promoted Cu I-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles.J.Org.Chem.2005,70,5164-5173.
[14]Rout,L.;Saha,P.;Jammi,S.;Punniyamurthy,T.Efficient Copper(I)-catalyzed C-S cross coupling of thiols with aryl halides in water.Eur.J.Org.Chem.2008,4,640-643.
[15]Kabir,M.S.;Lorenz,M.;Van Linn,M.L.A very active Cu-catalytic system for the synthesis of aryl,heteroaryl,and vinyl sulfides.J.Org.Chem.2010,75,3626-3643.
[16]Cameron,K.O.;Kung,D.W.;Kalgutkar,A.S.Discovery and preclinical characterization of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid(PF-06409577),a direct activator of adenosine monophosphate-activated protein kinase(AMPK),for the potential treatment of diabetic nephropathy.J.Med.Chem.2016,59,8068-8081.
[17]Tang,J.;Xie,B.;Bian,X.;Xue,Y.;Wei,N.;Zhou,J.;Hao,Y.;Li,Gang.;Zhang,L.;Wang,K.Identification and in vitro pharmacological characterization of a novel and selectiveα7 nicotinic acetylcholine receptor agonist,Br-IQ17B.Acta Pharmacol.Sin.2015,36,800-812.
[2](a)Seguela,P.;Wadiche,J.;Dineley-Miller,K.;Dani,J.A.;Patrick,J.W.Molecular cloning,functional properties,and distribution of rat brain alpha 7:A nicotinic cation channel highly permeable to calcium.J.Neurosci.1993,13,596-604.(b)Gotti,C.;Clementi,F.;Fornari,A.;Gaimarri,A.;Guiducci,S.;Manfredi,I.;Moretti,M.;Pedrazzi,P.;Pucci,L.;Zoli,M.Structural and functional diversity of native brain neuronal nicotinic receptors.Biochem.Pharmacol.2009,78,703-711.
[3](a)Xie,X.;Zhang,G.;Zhang,L.Advances onα7 n ACh Ras targets for drug development.Chin.J.Med.Chem.2015,25,313?323.(b)Hauser,T.A.;Kucinski,A.;Jordan,K.G.;Gatto,G.J.;Wersinger,S.R.;Hesse,R.A.;Stachowiak,E.K.;Stachowiak,M.K.;Papke,R.L.;Lippiello,P.M.;Bencherif,M.TC-5619:An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia.Biochem.Pharmacol.2013,355,32?37.(c)Wishka,D.G.;Walker,D.P.;Yates,K.M.;Reitz,S.C.;Jia,S.;Myers,J.K.;Olson,K.L.;Jacobsen,E.J.;Wolfe,M.L.;Groppi,V.E.;Hanchar,A.J.;Thornburgh,B.A.;Cortes-Burgos,L.A.;Wong,E.H.F.;Staton,B.A.;Raub,T.J.;Higdon,N.R.;Wall,T.M.;Hurst,R.S.;Walters,R.R.;Hoffmann,W.E.;Hajos,M.;Franklin,S.;Carey,G.;Gold,L.H.;Cook,K.K.;Sands,S.B.;Zhao,S.X.;Soglia,J.R.;Kalgutkar,A.S.;Arneric,S.P.;Rogers,B.N.Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide,An agonist of theα7 nicotinic acetylcholine receptor,for the potential treatment of cognitive deficits in schizophrenia:Synthesis and structure-activity relationship.J.Med.Chem.2006,49,4425?4436.
[4]Preskorn,S.H.;Gawryl,M.;Dgetluck,N.Normalizing effects of EVP-6124,an alpha-7 nicotinic partial agonist,on event-related potentials and cognition:a proof of concept,randomized trial in patients with schizophrenia.J.Psychiatr.Pract.2014,20,12?24.
[5](a)Williams,D.K.;Wang,J.;Papke,R.L.Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics:Advantages and limitations.Biochem.Pharmacol.2011,82,915-930.(b)Pandya,A.A.;Yakel,J.L.Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies.Biochem.Pharmacol.2013,86,1054-1062.
[6](a)Faghih,R.;Gopalakrishnan,M.;Briggs,C.A.Allosteric modulators of theα7 nicotinic acetylcholine receptor.J.Med.Chem.2008,51,701-712.(b)Gr?nlien,J.H.;Hakerud,M.;Ween,H.;Thorin-Hagene,K.;Briggs,C.A.;Gopalakrishnan,M.;Malysz,J.Distinct profiles ofα7 n ACh R positive allosteric modulation revealed by structurally diverse chemotypes.Mol.Pharmacol.2007,72,715-724.(c)Potasiewicz,A.;Ho?uj,M.;Kos,T.;Popik,P.;Arias,H.R.;Nikiforuk,A.3-Furan-2-yl-N-p-tolyl-acrylamide,a positive allosteric modulator of the a7 nicotinic receptor,reverses schizophrenia-like cognitive and social deficits in rats.Neuropharmacol.2017,113(Part A),188-197.
[7]Guerra-álvarez,M.;Moreno-Ortega,A.J.;Navarro,E.;Fernández-Morales,J.C.;Egea,J.;Lo?pez,M.G.;Cano-Abad,M.F.Positive allosteric modulation of alpha-7nicotinic receptors promotes cell death by inducing Ca2+release from the endoplasmic reticulum.J.Neurochem.2015,133,309-319.
[8](a)Gotti,C.;Clementi,F.;Zoli,M.Brain nicotinic acetylcholine receptors:Native subtypes and their relevance.Trends Pharmacol.Sci.2006,27,482?491.(b)Sharma,G.;Vijayaraghavan,S.Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores.Proc.Natl.Acad.Sci.USA.2001,98,4148?4153.(c)Yakel J.L.Nicotinic ACh receptors in the hippocampal circuit;functional expression and role in synaptic plasticity.J.Physiol.2014,592,4147?4153.
[9](a)Krause,R.M.;Buisson,B.;Bertrand,S.;Corringer,P.J.;Galzi,J.L.;Changeux,J.P.;Bertrand,D.Ivermectin:Apositive allosteric effector of theα7 neuronal nicotinic acetylcholine receptor.Mol.Pharmacol.1998,53,283?294.(b)Lopes,C.;Pereira,E.F.;Wu,H.Q.;Purushottamachar,P.;Njar,V.;Schwarcz,R.;Albuquerque,E.X.Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid atα7 nicotinic receptors.J.Pharmacol.Exp.Ther.2007,322,48?58.(c)Zwart,R.;Filippi,G.D.;Broad,L.M.;Mc Phie,G.I.;Pearson,K.H.;Baldwinson,T.;Sher,E.5-Hydroxyindole potentiates humanα7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices.Neuropharmacology.2002,43,374?384.(d)Gr?nlien,J.H.;H?kerud,M.;Ween,H.;Thorin-Hagene,K.;Briggs,C.A.;Gopalakrishnan,M.;Malysz,J.Distinct profiles ofα7 n ACh R positive allosteric modulation revealed by structurally diverse chemotypes.Mol.Pharmacol.2007,72,715?724.(e)Ng,H.J.;Whittemore,E.R.;Tran,M.B.;Hogenkamp,D.J.;Broide,R.S.;Johnstone,T.B.;Zheng,L.;Stevens,K.E.;Gee,K.W.Nootropicα7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators.Proc.Natl.Acad.Sci.USA.2007,104,8059?8064.(f)Timmermann,D.B.;Gr?nlien,J.H.;Kohlhaas,K.L.;Nielsen,E.?.;Dam,E.;J?rgensen,T.D.;Ahring,P.K.;Peters,D.;Holst,D.;Chrsitensen,J.K.;Malysz,J.;Briggs,C.A.;Gopalakrishnan,M.;Olsen,G.M.An allosteric modulator of theα7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.J.Pharmacol.Exp.Ther.2007,323,294?307.(g)Dunlop,J.;Lock,T.;Jow,B.;Sitzia,F.;Grauer,S.;Jow,F.;Kramer,A.;Bowlby,M.R.;Randall,A.;Kowal,D.;Gilbert,A.;Comery,T.A.;La Rocque,J.;Soloveva,V.;Brown,J.;Roncarati,R.Old and new pharmacology:Positive allosteric modulation of theα7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C)receptor antagonist SB-206553(3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']dipyrrole-1(2H)-carboxamide).J.Pharmacol.Exp.Ther.2009,328,766?776.(h)Broad,L.M.;Zwart,R.;Pearson,K.H.;Lee,M.;Wallace,L.;Mc Phie,G.I.;Emkey,R.;Hollinshead,S.P.;Dell,C.P.;Baker,S.R.;Sher,E.Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators.J.Pharmacol.Exp.Ther.2006,318,1108?1117.
[10](a)Huang,X.;Jiao,W.;Sun,Q.;Wang,K.Pharmacokinetic characterization of a novelα7 nicotinic acetylcholine receptor(n ACh R)positive allosteric modulator LD486 in rat plasma using a validated LC-MS/MS assay.J.Chin.Pharm.Sci.2016,25,517-525.(b)Wang,K.;Sun,Q.;Jiao,W.;Tang,J.Preparation of thiazolopyrimidinone compound and their medical use.Faming Zhuanli Shenqing.2017,CN 106279211 A 20170104(Patent in Chinese).
[11]Li,Y.H.;Sun,L.L.;Yang.T.Y.;Jiao,W.X.;Tang,J.S.;Huang,X.M.;Huang,Z.Z.;Meng,Y.;Luo,L.C.;Wang,X.T.;Bian,X.L.;Zhang,F.;Sun,Q.;Wang,K.W.Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice.J.Med.Chem.2018,DOI:10.1021/acs.jmedchem.7b01492.
[12]De Lucca,G.V.;Shi,Q.;Liu,Q.Small Molecule reversible inhibitors of Bruton's tyrosine kinase(BTK):Structure-activity relationships leading to the identification of 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide(BMS-935177).J.Med.Chem.2016,59,7915-7935.
[13]Zhang,H.;Cai,Q.;Ma,D.Amino acid promoted Cu I-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles.J.Org.Chem.2005,70,5164-5173.
[14]Rout,L.;Saha,P.;Jammi,S.;Punniyamurthy,T.Efficient Copper(I)-catalyzed C-S cross coupling of thiols with aryl halides in water.Eur.J.Org.Chem.2008,4,640-643.
[15]Kabir,M.S.;Lorenz,M.;Van Linn,M.L.A very active Cu-catalytic system for the synthesis of aryl,heteroaryl,and vinyl sulfides.J.Org.Chem.2010,75,3626-3643.
[16]Cameron,K.O.;Kung,D.W.;Kalgutkar,A.S.Discovery and preclinical characterization of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid(PF-06409577),a direct activator of adenosine monophosphate-activated protein kinase(AMPK),for the potential treatment of diabetic nephropathy.J.Med.Chem.2016,59,8068-8081.
[17]Tang,J.;Xie,B.;Bian,X.;Xue,Y.;Wei,N.;Zhou,J.;Hao,Y.;Li,Gang.;Zhang,L.;Wang,K.Identification and in vitro pharmacological characterization of a novel and selectiveα7 nicotinic acetylcholine receptor agonist,Br-IQ17B.Acta Pharmacol.Sin.2015,36,800-812.