RESUMEN
As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Piridinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Triazoles/farmacología , Administración Oral , Animales , Perros , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/síntesis química , Triazoles/farmacocinéticaRESUMEN
Kinetically controlled hydroboration of allenes 8 and 14a-d with the readily accessible Soderquist borane 7, which is generated in situ from borohydride 6, constitutes a convenient and preparatively useful method for synthesis of (Z)-gamma-(substituted)allylboranes 9 and 15a-d. These allylboranes undergo highly diastereo- (> or = 90: 10) and enantioselective (typically 89-96% e.e.) allylboration reactions with representative aldehydes to give syn-beta-functionalized homoallylic alcohols.
Asunto(s)
Alcadienos/química , Alcanos/química , Compuestos Alílicos/síntesis química , Boranos/síntesis química , Compuestos Bicíclicos con Puentes/química , Cinética , EstereoisomerismoRESUMEN
The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments.
Asunto(s)
Acetamidas/síntesis química , Piranos/síntesis química , Acetamidas/química , Animales , Piranos/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Estereoisomerismo , Urocordados/químicaRESUMEN
[reactiojn: see text] The enantioselective synthesis of (+)-rogioloxepane A has been achieved in 21 steps from 1,5-hexadien-3-ol. The key steps in the synthesis are an asymmetric glycolate alkylation leading to the diene 2 and a subsequent ring-closing metathesis to construct the oxepene core.