RESUMO
Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLEâ¯=â¯0.3, ΔFsp3â¯=â¯0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Further lead optimization on N-acyl-triazolopiperazine antagonists to the neurokinin-3 receptor (NK3R) based on the concurrent improvement in bioactivity and ligand lipophilic efficiency (LLE) is reported. Overall, compound 3 (LLE > 6) emerged as the most efficacious in castrated rat and monkey to lower plasma LH, and it displayed the best off-target safety profile that led to its clinical candidate nomination for the treatment of sex-hormone disorders.
RESUMO
Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Receptores da Neurocinina-3/antagonistas & inibidores , Relação Estrutura-Atividade , Androgênios/sangue , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO/efeitos dos fármacos , Células CACO-2/efeitos dos fármacos , Técnicas de Química Sintética , Cricetulus , Cristalografia por Raios X , Descoberta de Drogas , Canal de Potássio ERG1 , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Ligantes , Hormônio Luteinizante/sangue , Masculino , Ratos Sprague-Dawley , Receptores da Neurocinina-3/genéticaRESUMO
A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).
Assuntos
Flúor/química , Hidrocarbonetos/química , Cinética , Estrutura MolecularRESUMO
cis 5-tert-butyl-L-proline (Cbp) was prepared rapidly and efficiently by the addition of low-valent tert-butyl cuprate to an aminal derived from proline. [Cbp(2), D-Leu(5)]-OP was then synthesized, showing a predominant cis peptide bond conformation, as confirmed by NMR.
Assuntos
Cobre/química , Mimetismo Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/isolamento & purificação , Prolina/síntese químicaRESUMO
A highly diastereoselective and straightforward synthesis for (Z)-2-fluoroallylic alcohols via a Nozaki-Hiyama-Kishi-type reaction with the corresponding bromofluoroolefins was developed, providing an easy access to highly interesting fluorinated synthons.
Assuntos
Alcenos/síntese química , Hidrocarbonetos Fluorados/síntese química , Alcenos/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] Synthesis of 1-bromo-1-fluoroolefins was achieved in good yields via a Wittig reaction promoted by diethylzinc, even with nonactivated aldehydes and ketones as starting materials.