RESUMO
OBJECTIVES: The challenges of implementing clinical practice changes are well recognised. Prevailing approaches to tackling them have largely relied on increasing control and standardisation, but with limited impact. We examine research from the behavioural sciences in an attempt to (a) build a clearer understanding of why the implementation of change in clinical settings has proved so elusive and (b) provide practical guidance on how organisations can create a climate that can nurture sustained behavioural change in their workforce. METHOD: We undertook a review of the behavioural science literature to gain a better understanding of the circumstances under which staff might willingly pursue goals that are externally generated. Three studies, derived from the mental health literature, are outlined to illustrate how the manner in which change is introduced can have a significant effect on its uptake and sustainability. RESULTS: Research suggests that human behaviour is not as unpredictable as it might at first appear; rather, there are some deeply rooted, psychological processes at play. Self-Determination Theory, a theory of human motivation with an extensive body of research supporting its effectiveness, suggests that the manner in which change is introduced and implemented is critical. CONCLUSION: While improvement methodologies and the use of implementation strategies are necessary, experience would suggest that by themselves they are not sufficient. Overcoming the challenges of implementing change will require a significant shift in our thinking about organisational leadership and the way that change is introduced. Some practical ways leaders can foster staff buy-in for organisational change are proposed.
Assuntos
Liderança , Motivação , Humanos , Inovação Organizacional , Autonomia PessoalRESUMO
BACKGROUND: We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy. METHODS: Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate (combination-therapy group), methotrexate alone, or placebo for 39 weeks (double-blind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase. RESULTS: Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P=0.009 for combination therapy vs. methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P=0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P=0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group. CONCLUSIONS: In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.).
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Metotrexato/administração & dosagem , Receptores do Fator de Necrose Tumoral/administração & dosagem , Adulto , Idoso , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Imunoglobulina G/efeitos adversos , Infecções/etiologia , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Indução de Remissão , Suspensão de TratamentoRESUMO
This study presents genetic data for nine Native American populations from northern North America. Analyses of genetic variation focus on the Pacific Northwest (PNW). Using mitochondrial, Y chromosomal, and autosomal DNA variants, we aimed to more closely address the relationships of geography and language with present genetic diversity among the regional PNW Native American populations. Patterns of genetic diversity exhibited by the three genetic systems were consistent with our hypotheses: genetic variation was more strongly explained by geographic proximity than by linguistic structure. Our findings were corroborated through a variety on analytic approaches, with the unrooted trees for the three genetic systems consistently separating inland from coastal PNW populations. Furthermore, analyses of molecular variance support the trends exhibited by the unrooted trees, with geographic partitioning of PNW populations (FCT = 19.43%, p = 0.010 ± 0.009) accounting for over twice as much of the observed genetic variation as linguistic partitioning of the same populations (FCT = 9.15%, p = 0.193 ± 0.013). These findings demonstrate a consensus with previous PNW population studies examining the relationships of genome-wide variation, mitochondrial haplogroup frequencies, and skeletal morphology with geography and language.
Assuntos
Genética Populacional , Indígenas Norte-Americanos/genética , Filogenia , Cromossomos Humanos Y , Análise por Conglomerados , DNA Mitocondrial/genética , Emigração e Imigração , Variação Genética , Geografia , Humanos , Linguística , Noroeste dos Estados Unidos , Análise de Sequência de DNARESUMO
BACKGROUND: Psoriasis and psoriatic arthritis (PsA) impair quality of life, including reduction in employment or job duties. The PRESTA (Psoriasis Randomized Etanercept STudy in Patients with Psoriatic Arthritis) study, a randomized, double-blind, two-dose trial, examined the efficacy of etanercept treatment in patients with moderate-to-severe plaque psoriasis and PsA and the main results have been presented previously. This analysis examined employment status, job duties and sick days, pre-defined endpoints in PRESTA, among this patient population. METHODS: Participants (N=752) were randomized to receive etanercept 50 mg twice weekly (BIW; n=379) or 50 mg once weekly (QW; n=373) for 12 weeks by subcutaneous injection. All participants then received open-label etanercept 50 mg QW for 12 additional weeks, while remaining blinded to the randomization. A pharmacoeconomic questionnaire was administered at baseline, week 12 and week 24 of treatment. The questionnaire included employment status and changing job responsibilities and sick time taken due to psoriasis or PsA. The statistical methods included analysis of covariance, t-test, Fisher's exact test and McNemar's test. Last-observation-carried-forward imputation was used for missing data. RESULTS: Employment was at least maintained from baseline to week 24 in both dose groups (56% [BIW/QW] and 60% [QW/QW] at baseline, 61% and 60%, respectively, at week 24). Among employed participants, the proportion of patients whose job responsibilities changed due to PsA decreased significantly from baseline to week 24 (17-23% to 5-8%; p<0.01). Similar results were seen with job responsibility changes due to psoriasis (11-14% to 4%; p<0.01). The number of monthly sick days also decreased from baseline to week 24 (2.4 days for both treatment groups to 0.7 (BIW/QW) and 1.1 (QW/QW); p≤0.03 for each). No significant differences between the treatment groups were observed for any economic endpoint at any time point. CONCLUSIONS: For patients with moderate-to-severe plaque psoriasis and PsA, etanercept treatment resulted in reducing job responsibility changes due to disease and in reducing sick time. Effective treatment of psoriasis and PsA may reduce missed work days.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Emprego , Imunoglobulina G/uso terapêutico , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Licença Médica , Adulto , Artrite Psoriásica/economia , Efeitos Psicossociais da Doença , Método Duplo-Cego , Etanercepte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/economia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Our aim was to evaluate the implementation of joint crisis planning into routine clinical practice in community mental health services in Western Australia. METHOD: Four community mental health services, two metropolitan and two country based, were invited to participate in a 1-year pilot program to field test a crisis planning tool and the implementation process with a view to then rolling it out across Western Australia. Training and extensive support was offered to staff at the four sites. RESULTS: Consumers experienced the process as both empowering and therapeutic. Despite acknowledgement of the value of interagency collaboration in the planning process, almost all plans were completed by consumers with their case managers. The most conspicuous finding was the marked difference in the number of completed plans at each site. CONCLUSIONS: This study supports previous research findings that joint crisis planning enhances the therapeutic relationship and empowers consumers. Organisational readiness was a major factor in the differential uptake of crisis plans between sites. Our study highlights the critical importance of addressing the context and culture of each individual service in which a new intervention is being introduced as part of the implementation process.
Assuntos
Serviços Comunitários de Saúde Mental/métodos , Procedimentos Clínicos , Planejamento de Assistência ao Paciente/normas , Participação do Paciente/métodos , Adulto , Humanos , Projetos Piloto , Austrália OcidentalRESUMO
The C2 amination of imidazo[4,5-b]pyridines was accomplished through C2 halogenation followed by substitution (SNAr) with functionalized primary and secondary amines. This regioselective sequence is operationally simple and provides an easy access to derivatives of protected imidazo[4,5-b]pyridines.
RESUMO
MK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations, in vitro resistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Benzoxazinas/farmacologia , Ciclopropanos , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , HIV-1/genética , MutaçãoRESUMO
The EphA4 receptor and its ephrin ligands are involved in astrocytic gliosis following CNS injury. Therefore, a strategy aimed at the blockade of EphA4 signaling could have broad therapeutic interest in brain disorders. We have identified novel small molecule inhibitors of EphA4 kinase in specific enzymatic and cell-based assays. In addition, we have demonstrated in two in vitro models of scratch injury that EphA4 receptor kinase is activated through phosphorylation and is involved in the repopulation of the wound after the scratch. A potent EphA4 kinase inhibitor significantly inhibited wound closure and reduced the accumulation of the reactive astrocytes inside the scratch. We have also shown that after the transient focal cerebral ischemia in rats, a large glial scar is formed by the accumulation of astrocytes and chondroitin sulfate proteoglycan surrounding the infarcted tissue at 7 days and 14 days of reperfusion. EphA4 protein expression is highly up-regulated in the same areas at these time points, supporting its potential role in the glial scar formation and maintenance. Taken together, these results suggest that EphA4 kinase inhibitors might interfere with the astrogliosis reaction and thereby lead to improved neurological outcome after ischemic injury.
Assuntos
Gliose/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor EphA4/antagonistas & inibidores , Ferimentos e Lesões/patologia , Animais , Astrócitos/patologia , Western Blotting , Células CHO , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Gliose/patologia , Humanos , Imuno-Histoquímica , Ataque Isquêmico Transitório/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Ratos , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas , Cicatrização/efeitos dos fármacosRESUMO
Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Piridinas/química , Piridinas/farmacologia , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Animais , Linhagem Celular , Cães , HIV/enzimologia , Inibidores de Integrase de HIV/farmacocinética , Humanos , Ligação Proteica , Piridinas/farmacocinética , RatosRESUMO
In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).
Assuntos
Azepinas/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/síntese química , Imidazóis/farmacologia , Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Azepinas/química , Azepinas/farmacologia , Disponibilidade Biológica , Caprolactama/química , Células Cultivadas , Cães , Humanos , Imidazóis/química , Concentração Inibidora 50 , Macaca mulatta , Transtornos de Enxaqueca/tratamento farmacológico , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Piridonas/química , Inibidores da Transcriptase Reversa/síntese química , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , HIV/enzimologia , Transcriptase Reversa do HIV/metabolismo , Humanos , Estrutura Terciária de Proteína , Pirazóis/química , Piridinas/química , Piridonas/síntese química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
Studies were conducted to investigate mutation pathways among subtypes A, B, and C of human immunodeficiency virus type 1 (HIV-1) during resistance selection with nonnucleoside reverse transcriptase inhibitors (NNRTIs) in cell culture under low-multiplicity of infection (MOI) conditions. The results showed that distinct pathways were selected by different virus subtypes under increasing selective pressure of NNRTIs. F227C and Y181C were the major mutations selected by MK-4965 in subtype A and C viruses during resistance selection. With efavirenz (EFV), F227C and V106M were the major mutations responsible for viral breakthrough in subtype A viruses, whereas a single pathway (G190A/V106M) accounted for mutation development in subtype C viruses. Y181C was the dominant mutation in the resistance selection with etravirine (ETV) in subtype A, and E138K/H221Y were the mutations detected in the breakthrough viruses from subtype C viruses with ETV. In subtype B viruses, on the other hand, known NNRTI-associated mutations (e.g., Y181C, P236L, L100I, V179D, and K103N) were selected by the NNRTIs. The susceptibility of the subtype A and B mutant viruses to NNRTIs was determined in order to gain insight into the potential mechanisms of mutation development. Collectively, these results suggest that minor differences may exist in conformation of the residues within the NNRTI binding pocket (NNRTIBP) of reverse transcriptase (RT) among the three subtypes of viruses. Thus, the interactions between NNRTIs and the residues in the NNRTIBPs of different subtypes may not be identical, leading to distinct mutation pathways during resistance selection in cell culture.
Assuntos
Farmacorresistência Viral/genética , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular , Ciclopropanos , HIV-1/genética , Humanos , Estrutura Molecular , Mutação , Nitrilas , Pirazóis/química , Pirazóis/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas , Replicação Viral/efeitos dos fármacosRESUMO
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-L-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.
Assuntos
Inibidores da Protease de HIV/farmacologia , Lisina/análogos & derivados , Inibidores da Protease de HIV/química , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , RatosRESUMO
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Assuntos
Fármacos Anti-HIV/química , Éteres/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Inibidores da Transcriptase Reversa/química , Regulação Alostérica , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Cães , Éteres/síntese química , Éteres/farmacocinética , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Humanos , Mutação , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-AtividadeRESUMO
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the mainstays of therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, the effectiveness of NNRTIs can be hampered by the development of resistance mutations which confer cross-resistance to drugs in the same class. Extensive efforts have been made to identify new NNRTIs that can suppress the replication of the prevalent NNRTI-resistant viruses. MK-4965 is a novel NNRTI that possesses both diaryl ether and indazole moieties. The compound displays potency at subnanomolar concentrations against wild-type (WT), K103N, and Y181C reverse transcriptase (RT) in biochemical assays. MK-4965 is also highly potent against the WT virus and two most prevalent NNRTI-resistant viruses (viruses that harbor the K103N or the Y181C mutation), against which it had 95% effective concentrations (EC(95)s) of <30 nM in the presence of 10% fetal bovine serum. The antiviral EC(95) of MK-4965 was reduced approximately four- to sixfold when it was tested in 50% human serum. Moreover, MK-4965 was evaluated with a panel of 15 viruses with NNRTI resistance-associated mutations and showed a superior mutant profile to that of efavirenz but not to that of etravirine. MK-4965 was similarly effective against various HIV-1 subtypes and viruses containing nucleoside reverse transcriptase inhibitor or protease inhibitor resistance-conferring mutations. A two-drug combination study showed that the antiviral activity of MK-4965 was nonantagonistic with each of the 18 FDA-licensed drugs tested vice versa in the present study. Taken together, these in vitro data show that MK-4965 possesses the desired properties for further development as a new NNRTI for the treatment of HIV-1 infection.
Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Alcinos , Benzoxazinas/farmacologia , Linhagem Celular , Ciclopropanos , Farmacorresistência Viral , Humanos , Nevirapina/farmacologia , Nitrilas , Piridazinas/farmacologia , PirimidinasRESUMO
Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Sequência de Aminoácidos , Animais , Peptídeo Relacionado com Gene de Calcitonina/química , Dicroísmo Circular , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Piperidinas/química , Ligação Proteica , Transdução de Sinais , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indóis/síntese química , Compostos de Espiro/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Humanos , Indóis/farmacologia , Macaca mulatta , Oxindóis , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Quinolinas/química , Inibidores da Transcriptase Reversa/química , Sítio Alostérico , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Transcriptase Reversa do HIV/metabolismo , Conformação Molecular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/metabolismo , Quinolinas/síntese química , Quinolinas/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Tiocarbamatos/química , Tiocarbamatos/farmacologiaRESUMO
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.