- Identification of novel muscarinic M(3) selective antagonists with a conformationally restricted Hyp-Pro spacer.
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The identification of potent and selective muscarinic M(3) antagonists that are based on the recently discovered triphenylpropioamide derivative, 1, and have a unique amino acid spacer group is described. The introduction of a hydroxyproline-proline group to the spacer site and the use of a propyl or cyclopropylmethyl group as the piperidine N-substituent led to the discovery of the novel M(3) selective antagonists [8c, 8g; K(i)700-fold, M(2)/M(3)>180-fold], which have a more rigid structure than 1.
- Sagara, Yufu,Kimura, Toshifumi,Fujikawa, Toru,Noguchi, Kazuhito,Ohtake, Norikazu
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Read Online
- PYRAZOLE DERIVATIVES
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Disclosed are compounds of general formula (I), wherein R, R1, Rc, Rd, Re, Rf, X, Y, Z, A and B are as defined in the application.
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Paragraph 0152
(2013/04/23)
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- PYRAZOLE DERIVATIVES
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Disclosed are compounds of general formula (I), wherein R, R1, Rc, Rd, Re, Rf, X, Y, Z, A and B are as defined in the application.
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Paragraph 0268
(2013/06/26)
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- ORTHO PYRROLIDINE, BENZYL-SUBSTITUTED HETEROCYCLE CCR1 ANTAGONISTS FOR AUTOIMMUNE DISEASES and INFLAMMATION
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Compounds of the formula are disclosed. The compounds are CCR1 antagonists which are useful for the treatment and prevention of inflammatory and autoimmune diseases. Other embodiments are also disclosed.
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Page/Page column 39
(2009/04/24)
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- Large nonlinear effect observed in the enantiomeric excess of proline in solution and that in the solid state
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(Chemical Equation Presented) A clue to the origin of chirality? A solution of proline with high enantiomeric excess (85-99% ee) was obtained from solid proline of only 10% ee through novel dissolution and crystallization processes (see scheme). This observation may be an explanation for the origin of chirality on Earth.
- Hayashi, Yujiro,Matsuzawa, Masayoshi,Yamaguchi, Junichiro,Yonehara, Sayaka,Matsumoto, Yasunobu,Shoji, Mitsuru,Hashizume, Daisuke,Koshino, Hiroyuki
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p. 4593 - 4597
(2007/10/03)
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- Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity
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Identification of a novel class of potent and highly selective M 3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M3 selective antagonist that had > 100-fold selectivity versus the M1, M 2, M4, and M5 receptors (M3: K i = 0.30 nM, M1/M3 = 570-fold, M 2/M3 = 1600-fold, M4/M3 = 140-fold, M5/M3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M3 receptors.
- Sagara, Yufu,Sagara, Takeshi,Uchiyama, Minaho,Otsuki, Sachie,Kimura, Toshifumi,Fujikawa, Toru,Noguchi, Kazuhito,Ohtake, Norikazu
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p. 5653 - 5663
(2007/10/03)
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- Enzyme-catalyzed enantiomeric resolution of N-Boc-proline as the key-step in an expeditious route towards RAMP
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For the preparation of both enantiomers of N-carbamoyl-2-methoxymethylpyrrolidine, the precursors of Enders' chiral auxiliaries, SAMP and RAMP, enzyme-catalyzed kinetic resolution of racemic N-carbamoyl, N-Boc, N-Cbz proline esters and prolinols were examined. B. licheniformis protease (subtilisin) preferentially hydrolyzed the (R)-carbamoylproline ester with an enantiomeric ratio (E) of 10. To a hydrophobic N-Cbz proline ester, subtilisin showed lower selectivity (E=2.8), and in contrast, a purified protease (isozyme A) from the earthworm showed the preference of (S)-enantiomer (E=13.6). In a practical sense, C. antarctica lipase B (Chirazyme L-2) was effective for the hydrolysis of both N-Boc and N-Cbz derivatives with E >100. The e.e. of (R)-N-carbamoyl-2-methoxymethylpyrrolidine was raised to be >99.9% by recrystallization at the N-Boc-prolinol stage, which was derived from the (R)-N-Boc-proline methyl ester (98.7% e.e.) through a preparative-scale enzyme-catalyzed resolution (49% yield) of the racemic substrate.
- Kurokawa, Masayuki,Shindo, Takeyuki,Suzuki, Masumi,Nakajima, Nobuyoshi,Ishihara, Kohji,Sugai, Takeshi
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p. 1323 - 1333
(2007/10/03)
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- Facile new method for preparation of optically active protected proline
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Treatment of L-N-protected 2-amino-5-bromopentanoic acid ester, which was prepared from protected L-glutamic acid, with sodium hydride in tetrahydrofuran (THF) proceeded to give the corresponding protected L-proline in high yield. On the other hand, the reaction of 2-aminobutyric acid derivative with sodium hydride gave the 1-aminocyclopropane-1-carboxylic acid derivative.
- Yamaguchi, Jun-Ichi,Ueki, Masaaki
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p. 621 - 622
(2007/10/03)
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