RESUMO
A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB1R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB1R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.
Assuntos
Agonismo Inverso de Drogas , Quinolonas/química , Quinolonas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Proteica , Quinolonas/metabolismo , Quinolonas/farmacocinética , Ratos , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety.
Assuntos
Furanos/química , Furanos/farmacologia , Receptores CCR2/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/imunologia , Humanos , Receptores CCR2/imunologiaRESUMO
An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Naftiridinas/síntese química , Quinolinas/síntese química , Receptores de Vitronectina/antagonistas & inibidores , Naftiridinas/química , Naftiridinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Estereoisomerismo , Difração de Raios XRESUMO
Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Imidazóis/síntese química , Isoxazóis/síntese química , Pirazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Cristalografia por Raios X , Cães , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Permeabilidade , Ligação Proteica , Pirazóis/química , Pirazóis/farmacologia , Coelhos , Relação Estrutura-Atividade , Trombose/prevenção & controleRESUMO
As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Benzamidinas/farmacologia , Inibidores do Fator Xa , Guanidinas/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Anticoagulantes/farmacocinética , Sítios de Ligação/efeitos dos fármacos , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Desenho de Fármacos , Ligação de Hidrogênio , Indicadores e Reagentes , Absorção Intestinal , Mimetismo Molecular , Coelhos , Relação Estrutura-Atividade , Trombina/químicaRESUMO
A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.
Assuntos
Ansiolíticos/farmacologia , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Ansiolíticos/síntese química , Ansiolíticos/metabolismo , Transtornos de Ansiedade/tratamento farmacológico , Cães , Meia-Vida , Ligantes , Taxa de Depuração Metabólica , Piridinas/síntese química , Piridinas/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Escherichia coli under-expressing lepB was utilized to test cellular inhibition of signal peptidase I (SPase). For the construction of a lepB regulatable strain, the E. coli lepB gene was cloned into pBAD, with expression dependent on L-arabinose. The chromosomal copy of lepB was replaced with a kanamycin resistance gene, which was subsequently removed. SPase production by the lepB regulatable strain in the presence of various concentrations of L-arabinose was monitored by Western blot analysis. At lower arabinose concentrations growth proceeded more slowly, possibly due to a decrease of SPase levels in the cells. A penem SPase inhibitor with little antimicrobial activity against E. coli when tested at 100 micro M was utilized to validate the cell-based system. Under-expression of lepB sensitized the cells to penem, with complete growth inhibition observed at 10 to 30 micro M. Growth was rescued by increasing the SPase levels. The cell-based assay was used to test cellular inhibition of SPase by compounds that inhibit the enzyme in vitro. MD1, MD2, and MD3 are SPase inhibitors with antimicrobial activity against Staphylococcus aureus, although they do not inhibit growth of E. coli. MD1 presented the best spectrum of antimicrobial activity. Both MD1 and MD2 prevented growth of E. coli under-expressing lepB in the presence of polymyxin B nonapeptide, with growth rescue observed when wild-type levels of SPase were produced. MD3 and MD4, a reactive analog of MD3, inhibited growth of E. coli under-expressing lepB. However, growth rescue in the presence of these compounds following increased lepB expression was observed only after prolonged incubation.