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DOI 10.1021/jm200939b

Медицинская библиотека · Journal of medicinal chemistry · 2011

Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764).

Wager Travis T, Pettersen Betty A, Schmidt Anne W, Spracklin Douglas K, Mente Scot, Butler Todd W, Howard Harry, Lettiere Daniel J, Rubitski David M, Wong Diane F, Nedza Frank M, Nelson Frederick R, Rollema Hans, Raggon Jeffrey W, Aubrecht Jiri, Freeman Jody K, Marcek John M, Cianfrogna Julie, Cook Karen W, James Larry C, Chatman Linda A, Iredale Philip A, Banker Michael J, Homiski Michael L, Munzner Jennifer B, Chandrasekaran Rama Y

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Аннотация

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.

Для цитирования: Wager Travis T, Pettersen Betty A, Schmidt Anne W, Spracklin Douglas K, Mente Scot, Butler Todd W, Howard Harry, Lettiere Daniel J, Rubitski David M, Wong Diane F, Nedza Frank M, Nelson Frederick R, Rollema Hans, Raggon Jeffrey W, Aubrecht Jiri, Freeman Jody K, Marcek John M, Cianfrogna Julie, Cook Karen W, James Larry C, Chatman Linda A, Iredale Philip A, Banker Michael J, Homiski Michael L, Munzner Jennifer B, Chandrasekaran Rama Y. Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764).. Journal of medicinal chemistry. 2011. DOI: 10.1021/jm200939b.

Предметные рубрики MeSH

AnimalsBlood ProteinsBlood-Brain BarrierCell LineCyclobutanesDogsDrinking BehaviorDrug DesignHigh-Throughput Screening AssaysHistamine AntagonistsHumansIn Vitro TechniquesKidneyLipidosesLungMicrosomes, LiverModels, MolecularMolecular StructurePhospholipidsProtein BindingPyrrolidinesRatsRats, Sprague-DawleyReceptors, Histamine H3StereoisomerismStructure-Activity Relationship
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