RESUMEN
A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).
Asunto(s)
Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Administración Oral , Animales , Antineoplásicos/sangre , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Semivida , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Inyecciones Intravenosas , Macaca fascicularisRESUMEN
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Asunto(s)
Compuestos de Bifenilo/farmacocinética , Ácidos Hidroxámicos/farmacocinética , Inhibidores de la Metaloproteinasa de la Matriz , Administración Oral , Animales , Antineoplásicos/sangre , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/síntesis química , División Celular/efectos de los fármacos , Perros , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Semivida , Haplorrinos , Ácidos Hidroxámicos/sangre , Ácidos Hidroxámicos/síntesis química , Concentración 50 Inhibidora , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Neoplasias Experimentales/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Representative nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitors such as ibuprofen, naproxen, and indomethacin were used as orally bioavailable scaffolds to design selective 5-lipoxygenase (5-LO) inhibitors. Replacement of the NSAID carboxylic acid group with a N-hydroxyurea group provided congeners with selective 5-LO inhibitory activity.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Inhibidores de la Lipooxigenasa , Inhibidores de la Lipooxigenasa/síntesis química , Anafilaxia/tratamiento farmacológico , Anafilaxia/metabolismo , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Diseño de Fármacos , Humanos , Hidroxiurea/análogos & derivados , Ibuprofeno/química , Indometacina/química , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Leucotrieno E4/metabolismo , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacocinética , Inhibidores de la Lipooxigenasa/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Naproxeno/química , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Células Tumorales CultivadasRESUMEN
A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl. Molecular modeling suggests that the heterocyclic oxygen hydrogen bonds as an acceptor to the flap region of renin and that the second hydroxyl in the glycol-based inhibitors behaves similarly.
Asunto(s)
Carbamatos/farmacología , Furanos/farmacología , Compuestos Heterocíclicos , Lactonas/farmacología , Renina/antagonistas & inhibidores , Carbamatos/síntesis química , Fenómenos Químicos , Química , Furanos/síntesis química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Enlace de Hidrógeno , Lactonas/síntesis química , Conformación Molecular , Relación Estructura-ActividadRESUMEN
A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11 substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9 portion of the native substructure and employ novel phosphostatine Leu10-Val11 replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu10 side chain revealed that the LVR derived from L-cyclohexylalanine provided a 130-fold boost in potency over the LVR derived from L-leucine. The dialkyl ester moiety was varied and a loss in potency was incurred when the alkyl ester was chain extended or alpha-branched; dimethyl esters provided optimum potency. The phosphonate moiety was replaced by a half-acid half-ester phosphonate and dimethylphosphinate; both replacements lead to a loss in potency. The more potent inhibitors (IC50 = 20-50 nM) were found to be selective inhibitors for renin over porcine pepsin and bovine cathepsin D (little or no inhibition was observed at 10(-5) M).
Asunto(s)
Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Aminoácidos , Animales , Antihipertensivos , Catepsina D/antagonistas & inhibidores , Bovinos , Técnicas In Vitro , Leucina , Pepsina A/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Porcinos , ValinaRESUMEN
Stereoselective syntheses of several nonpeptide sulfidoethanol fragments that function as Leu10-Val11 (P1-P1') scissile bond replacements in human angiotensinogen are presented. These fragments are prepared from a variety of amino acids with formal P1 side chains varying in size and lipophilicity by converting them to their corresponding N-protected aminoalkyl epoxide 5 followed by ring opening with isopropyl mercaptan. The coupling of these fragments to either Boc-Phe-Ala-OH or Boc-Phe-His-OH produces inhibitors of human renin, 6 and 7, respectively, which are compared to a series of dipeptide-aldehyde inhibitors, 4, by molecular modeling and biochemical methods. Qualitatively, histidine-containing (P2) inhibitors 7 possess greater inhibitory potency than their corresponding alanine (P2) analogues 6, which are more potent than the corresponding aldehydic inhibitors from series 4. Within a given series, inhibitors with the cyclohexylmethyl P1 side chain are more potent than the benzyl analogues, which in turn are more potent than cyclohexyl or isobutyl derivatives. Inhibitors with parger P1 side chains (e.g. adamantylmethyl and benzhydryl) are much less active. The inhibitory potency of these compounds against human renin is discussed in terms of specific interactions with the enzyme.
Asunto(s)
Leucina , Renina/antagonistas & inhibidores , Valina , Secuencia de Aminoácidos , Angiotensinógeno/metabolismo , Sitios de Unión , Humanos , Concentración de Iones de Hidrógeno , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Further structure-activity relationships (SAR) for a novel dipeptide series inhibitors are reported. These inhibitors retain the Phe8-His9 portion of angiotensinogen and employ a unique Leu10-Val11 replacement [(LVR), ref 2]. SAR at the Leu10 side chain revealed that the LVR derived from cyclohexylalanine provided a nearly 10-fold boost in potency for the final inhibitor. In addition SAR work was carried out to delineate the relationships between binding potency and (1) the size, shape, and charge of the side chain at the His9 position; (2) the size and topology of the side chain at the Phe8 site; and (3) the size of the Phe8 N-protecting group. One of the more potent inhibitors, 12, was shown to provide a substantial antihypertensive effect in a sodium depleted monkey model when administered intravenously. Metabolism work, in Sprague-Dawley rats, provided insights into the susceptibility of 12 to significant hepatic clearance and provided encouraging evidence for intestinal absorption.