RESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Receptores de Superficie Celular/agonistas , Tiazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/metabolismo , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Receptores de Neuroquinina-3/antagonistas & inhibidores , Relación Estructura-Actividad , Andrógenos/sangre , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO/efectos de los fármacos , Células CACO-2/efectos de los fármacos , Técnicas de Química Sintética , Cricetulus , Cristalografía por Rayos X , Descubrimiento de Drogas , Canal de Potasio ERG1 , Enfermedades del Sistema Endocrino/sangre , Enfermedades del Sistema Endocrino/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Ligandos , Hormona Luteinizante/sangre , Masculino , Ratas Sprague-Dawley , Receptores de Neuroquinina-3/genéticaRESUMEN
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).
Asunto(s)
Flúor/química , Hidrocarburos/química , Cinética , Estructura MolecularRESUMEN
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.
Asunto(s)
Cobre/química , Imitación Molecular , Oligopéptidos/química , Oligopéptidos/farmacología , Prolina/análogos & derivados , Resonancia Magnética Nuclear Biomolecular , Oligopéptidos/aislamiento & purificación , Prolina/síntesis químicaRESUMEN
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.
Asunto(s)
Alquenos/síntesis química , Hidrocarburos Fluorados/síntesis química , Alquenos/química , Hidrocarburos Fluorados/química , Estructura Molecular , EstereoisomerismoRESUMEN
[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.