- Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin
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As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3- methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with Ki (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6′-iodononivamide.
- Kang, Dong Wook,Kim, Yong Soo,Lim, Kwang Su,Kim, Myeong Seop,Pearce, Larry V.,Pavlyukovets, Vladimir A.,Tao, Andy K.,Lang-Kuhs, Krystle A.,Blumberg, Peter M.,Lee, Jeewoo
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experimental part
p. 8092 - 8105
(2011/01/13)
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- 3-AMINO-INDAZOLE OR 3-AMINO-4,5,6,7-TETRAHYDRO-INDAZOLE DERIVATIVES
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This invention relates to novel indazole derivatives of formula I: wherein R1 to R7 are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are FXR modulators and can
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Page/Page column 22
(2010/04/23)
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- NOVEL EP4 RECEPTOR AGONIST COMPOUNDS
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A compound selected from the group consisting of: (3-chloro-4-{[(5-chloro-2-{[(2- chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; {4-[({5-chloro-2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; {3-chloro-4-[({5-chloro-2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; (3-chloro-4-{[(5-chloro-2-{[(3- chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; {4-[({2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; (4-{[(5-chloro-2-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}-2- fluorophenyl)acetic acid; {3-chloro-4-[({2-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; (3-chloro-4-{[(2-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; {4-[({2-chloro-6-[(phenylmethyl)oxy]phenyl}carbonyl)amino]phenyl}acetic acid; (4-{[(2-chloro-6-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetic acid; {4-[({5-chloro-2-[(phenylmethyl)amino]phenyl}carbonyl)amino]phenyl}acetic acid; (4-{[(5-chloro-2-{[(3-chlorophenyl)methyl]amino}phenyl)carbonyl]amino}phenyl)acetic acid; and (4-{[(5-chloro-2-{[(2-chlorophenyl)methyl]amino}phenyl)carbonyl]amino}phenyl)acetic acid, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine.
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Page/Page column 21
(2009/12/28)
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- Identification of 4-[1-[3-chloro-4-[N'-(5-fluoro-2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid as a potent, orally active VLA-4 antagonist
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Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid
- Muro, Fumihito,Iimura, Shin,Yoneda, Yoshiyuki,Chiba, Jun,Watanabe, Toshiyuki,Setoguchi, Masaki,Iigou, Yutaka,Takayama, Gensuke,Yokoyama, Mika,Takashi, Tohru,Nakayama, Atsushi,Machinaga, Nobuo
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experimental part
p. 9991 - 10000
(2009/04/06)
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- BENZO [F] ISOINDOLES AS EP4 RECEPTOR AGONISTS
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The present invention relates to naphthalene derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
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Page/Page column 26
(2008/06/13)
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- NOVEL ISOINDOL DERIVATIVES AS EP4 RECEPTOR AGONISTS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1, R2, R3, R4 and R5, X and Y are as defined in the specification; a process for preparing such compounds; a ph
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Page/Page column 29
(2008/06/13)
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- NAPHTHALENE DERIVATIVES USED AS EP4 RECEPTOR AGONISTS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1 R2 R3, X and Y are as defined in the specification; a process fo preparing such compounds; a pharmaceutical composition comprising
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Page/Page column 28
(2008/06/13)
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- BENZAMIDE DERIVATIVES AS EP4 RECEPTOR AGONISTS
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1, R2, R3, R4, R5, m, n and X are as defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprising such compounds; and the use of such compounds in medicine.
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Page/Page column 37-38
(2008/12/06)
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- ISOINDOL DERIVATIVES AS EP4 RECEPTOR AGONISTS
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The present invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
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Page/Page column 24
(2008/12/05)
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- BENZOISOINDOLE DERIVATIVES FOR THE TREATMENT OF PAIN
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A compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein, R1, R2, R3, X and Y are as defined in the specification; a process for preparing such compounds; a pharmaceutical composition comprisi
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Page/Page column 35
(2010/11/28)
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