Publications by authors named "Kazuaki Takami"

9 Publications

  • Page 1 of 1

Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

Bioorg Med Chem 2021 Jul 9;41:116208. Epub 2021 May 9.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.
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http://dx.doi.org/10.1016/j.bmc.2021.116208DOI Listing
July 2021

Design and Identification of a GPR40 Full Agonist () Possessing a 2-Carbamoylphenyl Piperidine Moiety.

J Med Chem 2020 09 9;63(18):10352-10379. Epub 2020 Sep 9.

Research Division, SCOHIA PHARMA Inc., Shonan Health Innovation Park, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic β-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative , we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine , which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with -alkyl--aryl benzamides to lower the lipophilicity and restrict the -alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential -alkyl--aryl benzamide. Among these, orally available (3)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid () effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00843DOI Listing
September 2020

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1)-one Derivatives as Orally eIF4A3-Selective Inhibitors.

ACS Med Chem Lett 2017 Oct 8;8(10):1077-1082. Epub 2017 Sep 8.

Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251-8555, Japan.

Starting from our previous eIF4A3-selective inhibitor , a novel series of (piperazine-1-carbonyl)pyridin-2(1)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds and showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds and showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642020PMC
October 2017

Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3-aminomethylquinolines: reducing human ether-a-go-go-related gene (hERG) associated liabilities.

J Med Chem 2012 May 23;55(9):4336-51. Epub 2012 Apr 23.

Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
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http://dx.doi.org/10.1021/jm300167zDOI Listing
May 2012

Stereoselective hydrothiolation of alkynes catalyzed by cesium base: facile access to (Z)-1-alkenyl sulfides.

J Org Chem 2005 Aug;70(16):6468-73

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

Treatment of alkyne with alkanethiol in the presence of a catalytic amount of cesium carbonate and a radical inhibitor in DMSO provides the corresponding adduct, (Z)-1-alkenyl alkyl sulfide, in good yield with high selectivity.
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http://dx.doi.org/10.1021/jo050931zDOI Listing
August 2005

Radical alkenylation of alpha-halo carbonyl compounds with alkenylindiums.

Org Lett 2004 Nov;6(24):4555-8

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.

Alkenylation reaction of alpha-halo carbonyl compounds with alkenylindiums proceeded via a radical process in the presence of triethylborane. Unactivated alkene moieties as well as a styryl group could be introduced by this method. The geometry of the carbon-carbon double bonds of the alkenylindiums was retained. Preparation of an alkenylindium via a hydroindation of 1-alkyne followed by radical alkenylation established an efficient one-pot strategy. [reaction: see text]
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http://dx.doi.org/10.1021/ol048070oDOI Listing
November 2004

Reaction of silyldihalomethyllithiums with nitriles: formation of alpha-keto acylsilanes via azirines and 1,3-rearrangement of silyl group from C to N.

J Am Chem Soc 2004 Jul;126(28):8618-9

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.

A synthesis of alpha-keto acylsilanes, where 2-bromo-2H-azirine participates as a key intermediate, is reported. The reaction of silyldibromomethyllithium with aryl nitriles provides alpha-keto acylsilanes in good yields. Interestingly, silyldichloromethyllithium induces aza-1,3-Brook rearrangement of the silyl group in th reaction with nitriles. The rearrangement enables a three-component coupling reaction in a one-pot operation.
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http://dx.doi.org/10.1021/ja047708oDOI Listing
July 2004

Triethylborane-mediated hydrogallation and hydroindation: novel access to organogalliums and organoindiums.

J Org Chem 2003 Aug;68(17):6627-31

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan.

Hydrogallation of carbon[bond]carbon multiple bonds proceeds in the presence of triethylborane as a radical initiator. Several functionalities do not interfere with this reaction. Resulting alkenyl- and alkylgallium species can be trapped by several electrophiles. Highly regioselective radical addition of an indium hydride reagent to alkynes is also achieved. Various functionalities are tolerant under the reaction conditions. The reaction proceeds with complete anti stereoselectivity. Alkenylindiums obtained via hydroindation can be employed for the following cross-coupling reaction with aryl halides in one pot.
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http://dx.doi.org/10.1021/jo0344790DOI Listing
August 2003

Trans-hydrometalation of alkynes by a combination of InCl3 and DIBAL-H: one-pot access to functionalized (Z)-alkenes.

Org Lett 2002 Aug;4(17):2993-5

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan.

[reaction: see text] Triethylborane-induced hydrometalation of alkynes proceeds in an anti manner to afford the corresponding (Z)-alkenylmetal compounds stereoselectively, where dichloroindium hydride would play a key role. A variety of functional groups including hydroxy, carbonyl, and carboxy groups were tolerant under the reaction conditions. Following iodolysis and cross-coupling reaction of the (Z)-alkenylmetal species show the usefulness of this strategy.
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http://dx.doi.org/10.1021/ol026401wDOI Listing
August 2002
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