34288-19-2Relevant academic research and scientific papers
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
Aylott, Helen E.,Atkinson, Stephen J.,Bamborough, Paul,Bassil, Anna,Chung, Chun-Wa,Gordon, Laurie,Grandi, Paola,Gray, James R. J.,Harrison, Lee A.,Hayhow, Thomas G.,Messenger, Cassie,Mitchell, Darren,Phillipou, Alexander,Preston, Alex,Prinjha, Rab K.,Rianjongdee, Francesco,Rioja, Inmaculada,Seal, Jonathan T.,Wall, Ian D.,Watson, Robert J.,Woolven, James M.,Demont, Emmanuel H.
, p. 3249 - 3281 (2021/04/06)
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
SUBSTITUTED 5-CARBOXYAMIDE PYRAZOLES AND [1,2,4]TRIAZOLES AS ANTIVIRAL AGENTS
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Page/Page column 54-55, (2008/06/13)
The present invention provides compounds of formula I wherein X, Y, R1-R7 are as defined herein. Compositions containing these compounds, and methods for inhibiting HCV RNA-dependent RNA polymerase and treating hepatitis C and related disorders using thes
Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V1a receptor
Kakefuda, Akio,Suzuki, Takeshi,Tobe, Takahiko,Tsukada, Junko,Tahara, Atsuo,Sakamoto, Shuichi,Tsukamoto, Shin-ichi
, p. 2589 - 2598 (2007/10/03)
A series of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives were prepared and evaluated as selective antagonists for the human vasopressin V1A receptor. The compounds were examined for their affinity to the cloned human V1A receptor (hV1A) and selectivity vs the cloned human V2 receptor (hV2). By utilizing the structure-activity relationship on 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydrobenzazepine derivatives as dual antagonists for the V1A and V2 receptors in our previous study, we found that substituting the methoxy group at the 2-position of the 4-phenyl ring with (4-methylpiperazin-1-yl)alkoxy moieties brought about marked improvement of both affinity to hV1A and selectivity vs hV2. Further introduction of a methyl group into the 6-position of the 4-phenyl ring resulted in additional improvement of selectivity. One particular compound, 5-(4-biphenyl)-3-methyl-4-{2-[6-(4-methyl-l-piperazinyl)-hexyloxy]phenyl} -1,2,4-triazole (19) showed potent affinity to hV1A with a Ki value of 1.04 nM and high selectivity with a 1700-fold selectivity vs hV2. We also found marked differences in the affinity of compounds in this series between the human and the rat receptors. Compound, 19 was further examined for its V1A receptor antagonist activity in rats. As a result, 19 demonstrated antagonist activities toward an arginine vasopressin-induced increase in diastolic blood pressure after intravenous or oral administration and long-lasting oral activity.
Discovery of 4,5-diphenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human V(1A) receptor.
Kakefuda, Akio,Suzuki, Takeshi,Tobe, Takahiko,Tahara, Atsuo,Sakamoto, Shuichi,Tsukamoto, Shin ichi
, p. 1905 - 1912 (2007/10/03)
In the search for a novel class of selective antagonists for the human V(1A) receptor, high-throughput screening (HTS) of the Yamanouchi chemical library using CHO cells expressing the cloned human V(1A) (hV(1A)) receptor led to the discovery of 5-(4-biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-triazole (3) which possessed the novel 4,5-diphenyl-1,2,4-triazole structure. Subsequent structure-activity relationships studies on a series of the 4,5-diphenyl-1,2,4-triazole derivatives related to 3 revealed that the 4,5-diphenyl-1,2,4-triazole structure played an essential role in exerting high affinity for the hV(1A) receptor and that introduction of a basic amine moiety to the methoxy part of the 4-phenyl ring was effective in the improvement of both affinity for the hV(1A) receptor and selectivity versus the hV(2) receptor. Compound 3 and the 2-(morphorino)ethoxy derivative (11b) were shown to be antagonists for the hV(1A) receptor, from their effects on AVP-induced [Ca(2+)](i) response in CHO cells expressing the hV(1A) receptor.
