RESUMO
Automated lead optimization helper application (ALOHA) is a novel fitness scoring approach for small molecule lead optimization. ALOHA employs a series of generalized Bayesian models trained from public and proprietary pharmacokinetic, absorption, distribution, metabolism, and excretion, and toxicology data to determine regions of chemical space that are likely to have excellent drug-like properties. The input to ALOHA is a list of molecules, and the output is a set of individual probabilities as well as an overall probability that each of the molecules will pass a panel of user selected assays. In addition to providing a summary of how and when to apply ALOHA, this paper will discuss the validation of ALOHA's Bayesian models and probability fusion approach. Most notably, ALOHA is demonstrated to discriminate between members of the same chemical series with strong statistical significance, suggesting that ALOHA can be used effectively to select compound candidates for synthesis and progression at the lead optimization stage of drug discovery.
Assuntos
Algoritmos , Desenho de Fármacos , Descoberta de Drogas , Preparações Farmacêuticas/análise , Software , Teorema de Bayes , Proteínas Sanguíneas/análise , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Humanos , Testes de Mutagenicidade , Estudos ProspectivosRESUMO
The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
Assuntos
Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Furanos/química , Furanos/farmacologia , Neuralgia/tratamento farmacológico , Piperazinas/química , Piperazinas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Analgésicos não Narcóticos/síntese química , Animais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Furanos/síntese química , Humanos , Masculino , Camundongos , Piperazinas/síntese química , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/síntese química , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.
Assuntos
Trifosfato de Adenosina/fisiologia , Óxidos S-Cíclicos/síntese química , Canais de Potássio/efeitos dos fármacos , Quinolonas/síntese química , Bexiga Urinária/efeitos dos fármacos , Animais , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Estimulação Elétrica , Cobaias , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Potenciais da Membrana , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Quinolonas/química , Quinolonas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Urodinâmica/efeitos dos fármacosRESUMO
Thiourea derivatives were identified as glyburide-reversible potassium channel openers through high-throughput screening. Based on these findings, a number of novel cyanoguanidines were designed and synthesized, which hyperpolarized human bladder K(ATP) channels. These agents are potent full agonists in relaxing electrically-stimulated pig bladder strips. The synthesis, SAR and biological properties of these agents are discussed.