122853-70-7Relevant academic research and scientific papers
6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.
Niiyama, Kenji,Mase, Toshiaki,Takahashi, Hirobumi,Naya, Akira,Katsuki, Kasumi,Nagase, Toshio,Ito, Satoshi,Hayama, Takashi,Hisaka, Akihiro,Ozaki, Satoshi,Ihara, Masaki,Yano, Mitsuo,Fukuroda, Takahiro,Noguchi, Kazuhito,Nishikibe, Masaru,Ishikawa, Kiyofumi
, p. 2461 - 2470 (2007/10/03)
Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.
Potent NK1 receptor antagonists: synthesis and antagonistic activity of various heterocycles with an N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarbamoyl substituent.
Ikeura,Tanaka,Kiyota,Morimoto,Ogino,Ishimaru,Kamo,Doi,Natsugari
, p. 1642 - 1652 (2007/10/03)
Various N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarbamoyl heterocycles (1, 2 and 3) modified at rings A and B in the isoquinolone (1a) and pyrido[3,4-b]pyridine (2a) nuclei were prepared and evaluated for NK1 receptor antagonistic activities. The structure-activity relationship studies on this series, along with conformational analysis, showed that (i) for ring A, 6-membered heterocycles are preferable to 5-membered heterocycles (a ca. 300-fold difference in potency), (ii) the 6-membered ring seems to function as an anchor by fixing the pendant phenyl group in a desirable orientation for receptor binding, and (iii) since compounds with aromatic rings (2) and those with aliphatic rings (3) as ring B both show good potency, this ring does not seem to be essential for receptor recognition. Among the compounds synthesized, the tetrahydropyridine derivatives 3a, 3b and 3f exhibited excellent inhibitory effects both in vitro and in vivo, with potent activity upon oral administration (ED50 = 0.20-0.27 mg/kg) (capsaicin-induced plasma extravasation in guinea pig trachea).
Heterocyclic compounds, their production and use as tachykinin reactor antagonists
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, (2008/06/13)
A novel compound represented by the formula: STR1 wherein Ring A and Ring B respectively stands for an optionally substituted homo- or hetero-cyclic ring, and at least one of them stands for an optionally substituted heterocyclic ring stand; Ring C stands for an optionally substituted benzene ring; R stands for a hydrogen atom or an optionally substituted hydrocarbon residue; one of X and Y stands for --NR1 -- (R1 stands for a hydrogen atom or an optionally substituted hydrocarbon residue) or --O--, and the other stands for--CO-- or --CS--, or one of them stands for --N= and the other stands for =CR2 -- (R2 stands for a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon residue, an optionally substituted amino group or an optionally substituted hydroxyl group); n denotes 1 or 2 or salts thereof which have an excellent tachykinin receptor antagonistic action and inhibitory action on plasma extravasation.
Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyridopyridine
Natsugari, Hideaki,Ikeura, Yoshinori,Kiyota, Yutaka,Ishichi, Yuji,Ishimaru, Takenori,et al.
, p. 3106 - 3120 (2007/10/02)
A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity.Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a.Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyridopyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists.Among the compounds synthesized, N--7,8-dihydro-N,7-dimethyl-8-oxo-5-(substituted phenyl)-6-pyridopyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of 125I>BH-SP binding in human IM-9-cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg.These compounds exhibited significantly potent activity upon oral adiministration with ED50 values of 0.068-0.17 mg/kg.Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.
Imidazolylphenyl and 1,2,4-triazolylphenyl benzopyridazinone and pyridopyridazinone compounds and their use for increasing cardiatonic contractility
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, (2008/06/13)
This invention relates to imidazolylphenyl and 1,2,4-triazolylphenyl benzopyridazinone and pyridopyridazinone compounds of the formula STR1 wherein A is CH or N and not more than one of W, X, Y and Z is a N atom which possess valuable pharmaceutical preparations, e.g., increasing cardiotonic contractility. Uses of said compounds including methods for increasing cardiac contractility and in the treatment of congestive heart failure, pharmaceutical compositions including the same and methods for the preparation thereof.
