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1.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

2.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

3.
J Pharm Sci ; 97(6): 2080-90, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17879292

RESUMO

A rapid-throughput screening assay was developed to estimate the salt solubility parameter, K(SP), with a minimal quantity of drug. This assay allows for early evaluation of salt limited solubility with a large number of counter-ions and biologically promising drug leads. Drugs dissolved (typically 10 mM) in DMSO are robotically distributed to a 96-well plate. DMSO is evaporated, and drugs are equilibrated with various acids at different concentrations (typically <1 M) to yield final total drug concentrations around 2.5 mM. The plate is checked for precipitation. Filtrates from only those precipitated wells were subjected to rapid gradient HPLC analysis. An iterative procedure is employed to calculate all species concentrations based on mass and charge balance equations. The apparent K(SP) values assuming 1:1 stoichiometry are determined from counter-ion and ionized drug activities. A correlation coefficient >0.975 for eight drugs totaling 16 salts is reported. Intra-day and inter-day reproducibility was <10%. Conventional apparent K(SP) measurements were translated to 96-well format for increased throughput and minimal drug consumption (typically 10 mg) to evaluate at least eight different counter-ions. Although the current protocol estimates K(SP) from 10(-3) to 10(-7) M, the dynamic range of the assay could be expanded by adjusting drug and counter-ion concentrations.


Assuntos
Microquímica , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Precipitação Química , Cromatografia Líquida de Alta Pressão , Dimetil Sulfóxido/química , Concentração de Íons de Hidrogênio , Modelos Químicos , Nefelometria e Turbidimetria , Reprodutibilidade dos Testes , Robótica , Solubilidade , Solventes/química
4.
J Pharm Sci ; 97(4): 1427-42, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17724660

RESUMO

A rapid solubility-screening assay was developed with a focus on Biopharmaceutic Classification Scheme (BCS) class II drug solubility in animal and simulated human gastrointestinal (GI) fluids. The assay enables biologically promising drug leads to be evaluated for solubility limitations earlier in the drug development process, minimizes GI fluid needs, and produces in vitro solubility information with potential in vivo implications. A number of BCS II drugs were dissolved in DMSO at approximately 40 mM, and robotically distributed to a 96-well plate. The DMSO was evaporated and drugs were equilibrated with selected GI fluids, both fed and fasted states. After equilibration, precipitated wells were subjected to HPLC analysis. A spreadsheet calculated solubility automatically from HPLC output. Intra-day, inter-day, and inter-plate reproducibility were within 15% RSTD for the tested drugs with the primary source of variability being injection precision of our injector system. The reported solubility from screening assays was well correlated with literature data (r(2) = 0.80) with a slope of 0.86 and (r(2) = 0.99) with a slope of 0.89. This screening assay converts conventional solubility measurements to a 96-well format for increased throughput (>12 samples/h), reduces fluid needs, and minimizes drug consumption.


Assuntos
Biofarmácia/métodos , Preparações Farmacêuticas/classificação , Solubilidade , Animais , Líquidos Corporais/metabolismo , Filtração , Trato Gastrointestinal/metabolismo , Humanos , Reprodutibilidade dos Testes
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