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Titolo:
Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1
Autore:
Ahmad, S; Doweyko, LM; Dugar, S; Grazier, N; Ngu, K; Wu, SC; Yost, KJ; Chen, BC; Gougoutas, JZ; DiMarco, JD; Lan, SJ; Gavin, BJ; Chen, AY; Dorso, CR; Serafino, R; Kirby, M; Atwal, KS;
Indirizzi:
Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Med Chem, Princeton, NJ08543 USA Bristol Myers Squibb Co Princeton NJ USA 08543 em, Princeton, NJ08543 USA Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Solid State Chem, Princeton, NJ 08543 USA Bristol Myers Squibb Co Princeton NJ USA 08543 m, Princeton, NJ 08543 USA Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Metab & Pharmacokinet, Princeton, NJ 08543 USA Bristol Myers Squibb Co Princeton NJ USA 08543 t, Princeton, NJ 08543 USA Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Metab & Cardiovasc DrugDiscovery, Princeton, NJ 08543 USA Bristol Myers Squibb Co Princeton NJ USA 08543 y, Princeton, NJ 08543 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 20, volume: 44, anno: 2001,
pagine: 3302 - 3310
SICI:
0022-2623(20010927)44:20<3302:AGANPA>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
NA+-H+ EXCHANGE; RAT NA/H EXCHANGER; MUSCLE CELLS; CARIPORIDE; EXPRESSION; CLONING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
23
Recensione:
Indirizzi per estratti:
Indirizzo: Ahmad, S Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Med Chem, POB 4000, Princeton, NJ 08543 USA Bristol Myers Squibb Co POB 4000 Princeton NJUSA 08543 08543 USA
Citazione:
S. Ahmad et al., "Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1", J MED CHEM, 44(20), 2001, pp. 3302-3310

Abstract

A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC50 = 3.5 muM) shows inhibitory activity comparable to cariporide (IC50 = 3.4 muM). Structure-activityrelationships are used to optimize the affinity of various acyl guanidinesfor NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobicgroups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC50 = 0.003 muM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 01:21:49