RESUMO
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Administração Oral , Analgésicos/sangue , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Humanos , Macaca mulatta , Camundongos , Piridinas/sangue , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Especificidade da Espécie , Compostos de Espiro/sangueRESUMO
Optimization studies using an HIV RNase H active site inhibitor containing a 1-hydroxy-1,8-naphthyridin-2(1H)-one core identified 4-position substituents that provided several potent and selective inhibitors. The best compound was potent and selective in biochemical assays (IC(50)=0.045 µM, HIV RT RNase H; 13 µM, HIV RT-polymerase; 24 µM, HIV integrase) and showed antiviral efficacy in a single-cycle viral replication assay in P4-2 cells (IC(50)=0.19 µM) with a modest window with respect to cytotoxicity (CC(50)=3.3 µM).
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/farmacologia , HIV-1/enzimologia , Ribonuclease H/antagonistas & inibidores , Fármacos Anti-HIV/química , Inibidores Enzimáticos/química , Células HeLa , Humanos , Naftiridinas/química , Naftiridinas/farmacologiaRESUMO
A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.
Assuntos
Inibidores de Integrase de HIV/química , Integrase de HIV , Pirazinas/química , Linhagem Celular Tumoral , Integrase de HIV/fisiologia , Inibidores de Integrase de HIV/farmacologia , Humanos , Pirazinas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/virologiaRESUMO
Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.
RESUMO
BACKGROUND: Migraine is a debilitating headache disorder which affects approximately 12% of the general population and is the cause of significant loss of productivity (i.e., lost time from work or school) for those afflicted. The current standard of care, the 5-HT(1B/1D) agonists known as triptans, is contraindicated in patients with cardiovascular disease due to their inherent vasoconstrictive activity; thus, there is a need to develop an alternative therapy for the treatment of the disorder. OBJECTIVE: This article reviews patent publications related to the use of small molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the treatment of migraine that have appeared in the literature within the past decade. The commentary is supplemented by information presented in journal articles and focuses on the activity of several major pharmaceutical companies in the field. CONCLUSION: Two small molecule CGRP receptor antagonists, olcegepant and telcagepant, have been shown to be clinically efficacious in the treatment of migraine, and thus provide validation of this novel therapeutic mechanism.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Desenho de Fármacos , Transtornos de Enxaqueca/tratamento farmacológico , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Indústria Farmacêutica , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Transtornos de Enxaqueca/fisiopatologia , Patentes como Assunto , Piperazinas , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismoRESUMO
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 6 is active against replication of HIV with a CIC(95) of 0.31 microM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Animais , Benzeno/química , Linhagem Celular , HIV/efeitos dos fármacos , HIV/enzimologia , HIV/fisiologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT=190 nM), excellent selectivity versus the digestive enzyme trypsin (K(i)=3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F=100%, CL=12 mL/min/kg).
Assuntos
Inibidores Enzimáticos/farmacologia , Prolina/análogos & derivados , Trombina/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformação Molecular , Prolina/química , Conformação Proteica , Estrutura Terciária de Proteína , Estereoisomerismo , Relação Estrutura-Atividade , Trombina/metabolismo , Tripsina/efeitos dos fármacos , Tripsina/metabolismoRESUMO
Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.