RESUMO
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%).
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Injeções Intravenosas , Macaca fascicularisRESUMO
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.
Assuntos
Compostos de Bifenilo/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/sangue , Compostos de Bifenilo/síntese química , Divisão Celular/efeitos dos fármacos , Cães , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Haplorrinos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/síntese química , Concentração Inibidora 50 , Injeções Intravenosas , Taxa de Depuração Metabólica , Neoplasias Experimentais/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/química , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/síntese química , Anafilaxia/tratamento farmacológico , Anafilaxia/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Humanos , Hidroxiureia/análogos & derivados , Ibuprofeno/química , Indometacina/química , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucotrieno E4/metabolismo , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacocinética , Inibidores de Lipoxigenase/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Naproxeno/química , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Células Tumorais CultivadasRESUMO
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.
Assuntos
Carbamatos/farmacologia , Furanos/farmacologia , Compostos Heterocíclicos , Lactonas/farmacologia , Renina/antagonistas & inibidores , Carbamatos/síntese química , Fenômenos Químicos , Química , Furanos/síntese química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Ligação de Hidrogênio , Lactonas/síntese química , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Aminoácidos , Animais , Anti-Hipertensivos , Catepsina D/antagonistas & inibidores , Bovinos , Técnicas In Vitro , Leucina , Pepsina A/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Suínos , ValinaRESUMO
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.
Assuntos
Leucina , Renina/antagonistas & inibidores , Valina , Sequência de Aminoácidos , Angiotensinogênio/metabolismo , Sítios de Ligação , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
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.