- Discovery of novel n-substituted prolinamido indazoles as potent rho kinase inhibitors and vasorelaxation agents
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Inhibitors of Rho kinase (ROCK) have potential therapeutic applicability in a wide range of diseases, such as hypertension, stroke, asthma and glaucoma. In a previous article, we described the lead discovery of DL0805, a new ROCK I inhibitor, showing potent inhibitory activity (IC50 6.7 μM). Herein, we present the lead optimization of compound DL0805, resulting in the discovery of 24- and 39-fold more-active analogues 4a (IC50 0.27 μM) and 4b (IC50 0.17 μM), among other active analogues. Moreover, ex-vivo studies demonstrated that 4a and 4b exhibited comparable vasorelaxant activity to the approved drug fasudil in rat aortic rings. The research of a preliminary structure-activity relationship (SAR) indicated that the target compounds containing a β-proline moiety have improved activity against ROCK I relative to analogues bearing an β-proline moiety, and among the series of the derivatives with a β-proline-derived indazole scaffold, the inhibitory activity of the target compounds with a benzyl substituent is superior to those with a benzoyl substituent.
- Yao, Yangyang,Li, Renze,Liu, Xiaoyu,Yang, Feilong,Yang, Ying,Li, Xiaoyu,Shi, Xiang,Yuan, Tianyi,Fang, Lianhua,Du, Guanhua,Jiao, Xiaozhen,Xie, Ping
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS
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The present application relates to a series of substituted pyrazolo[1,5-a]pyridine compounds, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.
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Paragraph 0670 - 0672
(2015/02/05)
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- Pyrrolidines
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This invention relates to a class of pyrrolidine compounds of formula (I), and pharmaceutically acceptable derivatives thereof, to their use in medicine, to compositions containing them, and to processes for their preparation. It also relates to intermedi
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Page/Page column 36
(2010/06/11)
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- QUINOLONE ANTIBACTERIAL AGENTS
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Compounds of formula (I) wherein A is formula (II), formula (III) or formula (IV), and B is formula (V), formula (VI), or formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 89; 90; 129; 130
(2010/02/12)
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- ANTIBACTERIAL AMINOQUINAZOLIDINEDIONE DERIVATIVES
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Compounds of formula (I) wherein: A is Formula (II), Formula (III), or Formula (IV) and B is Formula (V), Formula (VI), or Formula (VII), can be used in a variety of applications including use as antibacterial agents.
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Page/Page column 117; 118; 157; 158
(2010/02/12)
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- 1-(4-PIPERIDINYL) BENZIMIDAZOLONES AS HISTAMINE H3 ANTAGONISTS
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Disclosed are histamine H3 antagonists of the formula (I) wherein R1 is benzimidazolone derivative, M1 and M2 are optionally substituted carbon or nitrogen, R2 includes optionally substituted aryl or heteroaryl, and the remaining variables are as defined
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- Oxadiazoles useful in the treatment of senile dementia
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A class of novel oxadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring, and substituted on the other ring carbon atom with a substituent of low lipophilicity; are potent muscarinic agonists, and have good CNS penetrability. The compounds are therefore useful in the treatment of neurological and mental illnesses.
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- THIADIAZOLES USEFUL IN THE TREATMENT OF SENILE DEMENTIA
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A class of novel thiadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity, or a hydrocarbon substituent; are potent muscarinic agonists, and have good CNS penetrability. The compounds are therefore useful in the treatment of neurological and mental illnesses, and are also of benefit in the treatment of severe painful conditions.
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- β-Proline Analogues as Agonists at the Strychnine-Sensitive Glycine Receptor
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3-Carboxy-3,4-dehydropyrrolidine was found to bind with affinity equal to that of glycine in a strychnine binding assay.Simple substitution of the 1-, 2-, 4-, or 5-position resulted in marked loss of affinity.A decaline in affinity was also found upon
- Johnson, Graham,Drummond, James T.,Boxer, Peter A.,Bruns, Robert F.
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p. 233 - 241
(2007/10/02)
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