RESUMO
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Modelos Estatísticos , Testes de Toxicidade/métodos , Animais , Análise Discriminante , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismoRESUMO
Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.
Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Nervos Periféricos/efeitos dos fármacos , Ácidos Fosfínicos/farmacologia , Propilaminas/farmacologia , Animais , Autorradiografia , Baclofeno/farmacologia , Ligação Competitiva/efeitos dos fármacos , Cálcio/metabolismo , Cães , Relação Dose-Resposta a Droga , Esfíncter Esofágico Inferior/inervação , Feminino , Furões/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Humanos , Hipotermia/induzido quimicamente , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Relaxamento Muscular/efeitos dos fármacos , Ligação Proteica , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/metabolismo , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologiaRESUMO
Cannabinoid ligands are implicated in many physiological processes and to date two receptors have been identified. However, a growing body of evidence exists that suggests the presence of additional receptors. Whilst cloning the previously described hCB1a, we have identified a novel variant that we call hCB1b. Characterising these two splice variants demonstrates that they have a unique pharmacological profile and that their RNA's are expressed at low levels in a variety of tissues.
Assuntos
Processamento Alternativo , Receptor CB1 de Canabinoide/genética , Sequência de Aminoácidos , Ligação Competitiva , Canabinoides/química , Canabinoides/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Expressão Gênica , Biblioteca Gênica , Guanosina 5'-O-(3-Tiotrifosfato)/química , Humanos , Ligantes , Dados de Sequência Molecular , Receptor CB1 de Canabinoide/metabolismoRESUMO
The effects of the novel GABA analogue (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA(A)/GABA(B) selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55 +/- 8% after intragastric administration of AFPSiA at 14 mumol kg(-1) and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37 +/- 6 and 16 +/- 9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 micromol kg(-1). The oral availability of AFPSiA was 52 +/- 17 and 71 +/- 4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)-(3-amino-2-fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA(B) (K(i) =47 +/- 4.4 nM) compared to GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA(A) (K(i) = 37 +/- 3.1 nM) vs GABA(B) (K(i) = 6800 +/- 280 nM) receptors. In the mouse, high doses (1-8 mmol kg(-1)) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg(-1)). This effect was unaffected by the selective GABA(B) receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg(-1)) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg(-1).It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA(A) receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.
Assuntos
Esfíncter Esofágico Inferior/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Relaxamento Muscular/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Deglutição/efeitos dos fármacos , Cães , Esfíncter Esofágico Inferior/fisiologia , Feminino , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-B , Hipotermia/induzido quimicamente , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Ácidos Sulfínicos/efeitos adversos , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismoRESUMO
2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazoles (2, sulfides) exhibit antibacterial properties that are selective for Helicobacter spp., but they also have an inherent susceptibility to metabolic oxidation to furnish 2-[[(2-pyridyl)methyl]sulfinyl]-1H-benzimidazoles (1), which act as proton pump inhibitors (PPIs). We have discovered five compounds with retained antibacterial potency and selectivity in which the overall framework of the sulfides 2 could be kept intact while structural modifications were made to remove PPI activity. These compounds, 2-[((2-methyl-3-(2-(2-(2-methoxyethoxy)ethoxy)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (79), 2-[((2-methyl-3-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (80), 2-[((2-methyl-3-((2-morpholino)ethylthio)phenyl)methyl)thio]-1H-benzimidazole (86), 2-[[[2-methyl-3-[2-(2-methyl-5-nitroimidazol-1-yl)ethylthio]phenyl]methyl]thio]-1H-benzimidazole (88), and 2-[[[2-methyl-3-[2-(1,2,4-triazol-1-yl)ethylthio]phenyl]methyl]thio]-1H-benzimidazole (89), had minimum bactericidal concentrations (MBCs) of 0.5, 0.5, 1, 2, and 4 microg/mL, respectively. The reported compounds are bactericidal with MBCs within 1 order of magnitude of MBCs of clinically used antimicrobials such as clarithromycin (0.1 microg/mL) or metronidazole (2-4 microg/mL) but differ from these inasmuch that they have an extremely narrow spectrum activity and appear to be species specific.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/síntese química , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Doing the right things or doing things right: what is the most important focus for current drug discovery to secure delivery of new drugs of sustainable value to patients, healthcare professionals and healthcare providers? Some of the challenges faced today in drug discovery are addressed here: the relationship between R&D speed, cost and quality; how selection of performance metrics can affect the quality of the R&D output; the importance of leadership and management; how process orientation can affect, for example, creativity and innovation; the importance of selecting the right pharmacologic target and the right chemical lead; and why the use of drug-target kinetic and thermodynamic data to drive lead selection and lead optimization could increase success rates.
Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Custos e Análise de Custo , Descoberta de Drogas/economia , Indústria Farmacêutica/economia , Indústria Farmacêutica/organização & administração , Humanos , Liderança , Terapia de Alvo Molecular , Inovação Organizacional , Pesquisa/economia , Pesquisa/organização & administração , Pesquisa/normas , Termodinâmica , Fatores de TempoRESUMO
The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.
Assuntos
Química Farmacêutica/métodos , Química Farmacêutica/normas , Animais , Química Farmacêutica/tendências , Humanos , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/normas , Controle de Qualidade , Fatores de TempoRESUMO
We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.
Assuntos
Agonistas GABAérgicos/química , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B , Refluxo Gastroesofágico/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Agonistas GABAérgicos/uso terapêutico , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
A scaffold hopping approach has been exploited to design a novel class of cannabinoid (CB1) receptor antagonists for the treatment of obesity. On the basis of shape-complementarity and synthetic feasibility the central fragment, a methylpyrazole, in Rimonabant was replaced by a pyrazine. The synthesis and CB1 antagonistic activities of a new series of 5,6-diaryl-pyrazine-2-amide derivatives are described. Several compounds showed antagonist potency below 10nM for the CB1 receptor.