- ANTIVIRAL PYRIDOPYRAZINEDIONE COMPOUNDS
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The invention provides compounds of Formula (I) as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods to use these compounds, salts and compositions for treating viral infections, particularly infections caused by herpesviruses.
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Paragraph 0610; 0612
(2020/04/09)
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- Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists
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Hit optimization of the class of quinazoline containing histamine H 4 receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline4-amino)-N- phenylethanesulfonamide (54) (pki = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
- Smits, Rogier A.,Adami, Maristella,Istyastono, Enade P.,Zuiderveld, Obbe P.,Van Dam, Cindy M. E.,De Kanter, Frans J. J.,Jongejan, Aldo,Coruzzi, Gabriella,Leurs, Rob,De Esch, Iwan J. P.
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supporting information; experimental part
p. 2390 - 2400
(2010/09/11)
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- Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl- octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin
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The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2′ modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.
- G?schke, Richard,Stutz, Stefan,Rasetti, Vittorio,Cohen, Nissim-Claude,Rahuel, Joseph,Rigollier, Pascal,Baum, Hans-Peter,Forgiarini, Peter,Schnell, Christian R.,Wagner, Trixie,Gruetter, Markus G.,Fuhrer, Walter,Schilling, Walter,Cumin, Frédéric,Wood, Jeanette M.,Maibaum, Jürgen
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p. 4818 - 4831
(2008/03/13)
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- Synthesis and biological properties of new 1β-methylcarbapenems
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The synthesis and biological activity of the novel series of 1β- methylcarbapenems, 1 and 2 were described. Most compounds displayed high potent antibacterial activity. The best compound in this series, 2a (IH201; R2=NH2) showed an excellent and a broad spectrum as well as high renal DHP- I stability. It also possessed good in vivo efficacy and high safety.
- Shin, Kye Jung,Yoo, Kyung Ho,Kim, Dong Jin,Park, Sang Woo,Ko, Bong Suck,Lee, Sang Joo,Huh, Jae Doo,Park, Seung Yong
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p. 1607 - 1612
(2007/10/03)
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