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Language：English   Publishing type：Research paper (scientific journal)  

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Drug design using boron‐containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron‐containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro‐fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro‐fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron‐containing compounds are therefore eligible for classification in a novel chemical library.

DOI： 10.1111/cbdd.13496

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DOI： 10.3987/COM-18-S(F)87

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Using a novel tandem reduction-cyclization, we synthesized t-butyl 3-alkyloxindole-3-carboxylates from the di-t-butyl 2-alkyl-2-(2-nitrophenyl)malonate. Introduction of an alpha-substituent to the di-t-butyl 2-(2-nitrophenyl)-malonates and addition of acid promoted reactivity. This methodology was successfully applied to gram-scale-synthesis of the t-butyl 3-methyloxindole-3-carboxylate 1 and 3-hydroxyrnethy1-3-methyloxindole 2 without silica gel column chromatography.

DOI： 10.3987/COM-17-S(T)2

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Language：English   Publishing type：Research paper (scientific journal)  

We designed and synthesized a pyrilamine derivative 1 as a selective class I HDAC inhibitor that targets pyrilamine-sensitive proton-coupled organic cation antiporter (PYSOCA) at the blood-brain barrier (BBB). Introduction of pyrilamine moiety to benzamide type HDAC inhibitors kept selective class I HDAC inhibitory activity and increased BBB permeability. Our BBB transport study showed that compound 1 is a substrate of PYSOCA. Thus, our findings suggest that the hybrid method of HDAC inhibitor and substrate of PYSOCA such as pyrilamine is useful for development of HDAC inhibitors with increased BBB permeability.

DOI： 10.1021/acsmedchemlett.8b00099

PubMed

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DOI： 10.3987/COM-18-S(T)82

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A practical and chromatography-free synthetic process to selective M-1 and M-4 muscarinic acetylcholine receptors agonist was developed and demonstrated on a several hundred gram scale. The key feature of this route is N,N- dimethylcarbamoylation of the anilinic nitrogen on the spiro 7-azaindoline structure via intermolecular migration of the NjN- dimethylcarbamoyl group. The resulting compound 1 was prepared in 43% overall yield with a chemical purity >99% via six steps starting with (2-chloropyridin-3-yl)acetonitrile.

DOI： 10.1021/acs.oprd.7b00236

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Although several p53-Mdm2-binding disruptors have been identified to date, few studies have been published on p53-Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200-300 selectively inhibited the p53-Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53-Mdmx interaction over the p53-Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53-Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100 mg/kg and 150 mg/kg, respectively, in 40 days. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2016.03.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We designed and synthesized a series of dihydroquinazolinone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M-1 and M-4 muscarinic acetylcholine receptors with M-4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50 = 3.0 mg/kg, sc). (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2015.09.032

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The chiral diether ligand-controlled asymmetric conjugate addition of organolithiums to nona-2,7-dienedioate and subsequent intramolecular conjugate addition of the enolate intermediate gave alltrans trisubstituted cyclohexanes with high ee and yields. Using this methodology, an efficient short asymmetric total synthesis of (+)-beta-lycorane was accomplished in 33% overall yield through five steps from the dienedioate. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2015.03.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

The chiral diether ligand controlled asymmetric conjugate addition of organolithiums to nona-2,7-dienedioates preferentially proceeds via the s-cis conformation with coordination of the carbonyl oxygen atom to the lithium to give a lithium E-enolate intermediate. Subsequent intramolecular conjugate addition of the enolate also proceeds via a cyclic transition state involving the lithium and the s-cis-enoate, resulting in trans,trans-trisubstituted cyclohexanes with high enantiomeric excesses and yields.

DOI： 10.1055/s-0034-1380702

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DOI： 10.1055/s-0034-1380721

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We designed and synthesized novel N-sulfony1-7-azaindoline derivatives as selective M-4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M-4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound I, a selective M-4 mAChR agonist. Compound 1 showed a highly selective M-4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po). (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2014.04.083

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M-1 and M-4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2014.04.085

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We describe here the synthesis of [C-14]-2-(3-chlorophenyloxy)-3-[3-(3-hydroxy) pyridin-4-yl propoxy] pyridine (1), a phosphodiesterase 4 inhibitor. [C-14]-Labeled 1 was prepared in three steps from [C-14]-2-bromopyridin-3-ol in an overall yield of 32%. Preparation of [C-14]-labeled 2 and 3, two metabolites of 1, is also described.

DOI： 10.1002/jlcr.3211

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2014.04.052

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

Modulation of muscarinic acetylcholine receptors (mAChRs) is one of the most attractive therapeutic strategies for the treatment of schizophrenia. Pilot clinical studies of the M1/M4 mAChR-preferring agonist xanomeline as well as animal studies using M1–M5 mAChR knockout mice suggest that selective activation of M1 and/or M4 mAChRs is a key concept in the treatment of psychosis and cognitive deficits in patients with schizophrenia. However, over the past two decades, clinical development of mAChR agonists has not been successful mainly due to these agents’ narrow safety margin caused by the lack of true subtype selectivity. However, recent advances in medicinal chemistry might enable researchers to overcome the hurdles that earlier mAChR agonists failed to pass. Here, we describe recent advances in the development of subtype-selective mAChR activators for treatment of schizophrenia.

DOI： 10.1007/7355_2014_47

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

N,N-Dimethylcarbamoylation of the anilinic nitrogen atom N(1) on the spiro 7-azaindoline consists of two steps. The first step is N,N- dimethylcarbamoylation of the pyridyl nitrogen atom N(7), leading to the formation of an isolable intermediate. The second step is intermolecular migration of the N,N-dimethylcarbamoyl group from the pyridyl nitrogen atom N(7) to the anilinic nitrogen atom N(1). We accomplished optimization of the reaction conditions based on the revealed reaction mechanism and a large scale synthesis of compound 3 in quantitative yield. © 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2013.09.024

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2013.07.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M-1 and M-4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2013.06.013

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Language：English   Publishing type：Research paper (scientific journal)  

Activation of the M1 and M4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M1 and M4 over M2, M3, and M 5. Among these oxindoles, compound 1 showed high selectivity for the M1 and M4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects. © 2013 American Chemical Society.

DOI： 10.1021/ml300372f

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

We describe in this study the asymmetric synthesis of radioisotope (RI)-labeled selective glucocorticoid receptor modulator. This synthesis is based on optimization of the cinchona alkaloid catalyzed addition of 6-bromoindole to ethyl trifluoropyruvate and Negishi coupling of zinc cyanide to the 6-bromoindole moiety. [C-14] Labeled (-)-{4-[(1-{2-[6-cyano-1-(cyclohexylmethyl)-1H-indol-3-yl]-3,3,3-trifluoro-2-hydroxypropyl} piperidin-4-yl)oxy]-3-methoxyphenyl}acetic acid (-)-1 was synthesized successfully with high enantioselectivity (> 99% ee) and sufficient radiochemical purity.

DOI： 10.3390/molecules17066507

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have successfully synthesized enantiomerically pure (+)- and (-)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (-)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (-)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (-)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (-)-3 showed a higher binding affinity compared to (+)-3. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetasy.2011.01.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ol9003564

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

We have been involved in development of asymmetric reactions using diether 2 as a chiral chelating ligand and have succeeded in asymmetric addition of organolithium reagents to α,β-unsaturated carboxylates (Scheme 1). The addition of organolithium reagent to α,β-unsaturated carboxylate gives lithium enolate intermediate, whose intermolecular trapping with another α,β-unsaturated carboxylate moiety would produce highly functionalized chiral cyclohexane building blocks, such as 4 (Scheme 2). We planned asymmetric synthesis of Amaryllidaceae alkaloids, lycorine (1) and related compounds using 4 as a key intermediate. The investigation of the key tandem asymmetric conjugate addition-cyclization reaction using chiral ligand 2 revealed that the bulky ortho-substituent, TMS group of aryllithium 6b using important to achieve the first addition step in high enantioselectivity (Scheme 3). Besides, the ethylenedioxy group of α,β-unsaturated carboxylate 3 improves diastereoselectivity in the cyclization step probably because the replacement of H with O makes 1,3-diaxial interaction more unfavorable in the transition state that gives trans-cis isomers 8 (Figure 2). With enantiomerically enriched cyclohexane 9 in hand, we started the asymmetric synthesis of lycorines (Scheme 4). Treatment of 9 with ethanolic HCl gave carboxylic acid 10, whose Curtius rearrangement gave carbamate 11 in good yield. Formation of the tetracyclic core was achieved via lactam formation and Bishler-Napieralski reaction to give ketone 14. Formal synthesis of 1-deoxylycorine was accomplished via double bond formation by IBX oxidation of silyl enolate and reduction of the resulting enone 15. Introduction of 2-hydroxy functionality to ketone 14 was achieved stereoselectively by Magnus' chemistry (Scheme5). Formation of double bond followed by reduction gave 2-epi-lycorine diacetate (23) after acetylation of the resulting 2-epi-lycorine (22).

DOI： 10.24496/tennenyuki.49.0_211

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A series of 10 didodecanoylamides of alpha,omega-alkylidenediamines bridged by a straight carbon chain varying in length from 0 to 9 carbons was examined as possible gelator molecules of organic liquids to gain information on the relationships between the spacial arrangement of two amide groups in a molecule and their effects on the microscopic structures of the gel. The structural characteristics of these amides are parallel and antiparallel arrangements of two amide carbonyl groups, which depend on the even and odd numbers of a bridging zigzag carbon chain. The linear alkyl chain moieties and a center carbon chain of diamides intermolecularly interact with each other within the van der Waals contact. Two amide moieties of an even number carbon chain diamide intermolecularly interact with each other by using two pairs of hydrogen bonds with two other molecules in a plane, which formed ribbonlike self-complementarily assembled aggregates. On the other hand, a diamide of an odd number carbon chain forms four independent hydrogen bonds with four other molecules not in a plane, which assembled into woven aggregates. Asymmetric introduction of a methyl group at the alpha-position of the amide groups successfully twists the two side chain van der Waals cores of the chiral diamides in the fixed direction, giving helically twisted ribbon and coiled coil aggregates. The helically twisted ribbon and coiled coil aggregates of these chiral diamides were directly observed by CD, SEM, and TEM, providing a basis for the design of a sophisticated small molecular gelator of a tailor-made shape.

DOI： 10.1021/ja035085t

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja0169318

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Grant-in-Aid for Scientific Research 200004-200303

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