RESUMEN
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
Asunto(s)
Descubrimiento de Drogas , Pirazoles/farmacología , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Pirazoles/administración & dosificación , Pirazoles/química , Pirrolidinas/químicaRESUMEN
BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.
Asunto(s)
Descubrimiento de Drogas/métodos , Receptores de Ghrelina/agonistas , Tetrazoles , Carbamatos , Humanos , Proyectos de InvestigaciónRESUMEN
A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.
Asunto(s)
Diterpenos/química , Indoles/síntesis química , Aldehídos/química , Alquilación , Compuestos de Anilina/química , Alcohol Bencilo/química , Compuestos de Bencilo/química , Éteres/química , Hidrazonas/química , Indoles/química , Lactonas/química , Estructura Molecular , Estereoisomerismo , Toluidinas/químicaRESUMEN
A second-generation strategy for construction of (+)-nodulisporic acids A and B based on the development of a new, effective modular indole synthesis exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic is disclosed. This strategy evolved due to the considerable acid instability of the C(24) hydroxyl group observed in several advanced intermediates during our first-generation approach.
Asunto(s)
Diterpenos/síntesis química , Indoles/síntesis química , Aminación , Compuestos de Anilina/química , Cristalografía por Rayos X , Ciclización , Diterpenos/química , Indoles/química , Cinética , Lactonas/química , Modelos Moleculares , Estructura Molecular , TermodinámicaRESUMEN
[reaction: see text] Construction of the highly strained CDEF parent tetracycle, a structural motif found only in the potent ectoparasiticidal agents (+)-nodulisporic acids A and B and related congeners, has been achieved via a new modular indole synthesis, exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic. The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted indoles possessing uncommon substitution patterns.
Asunto(s)
Indoles/síntesis química , Ciclización , Indoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
[structure: see text] A stereocontrolled total synthesis of (+)-nodulisporic acid F, the simplest member of a family of novel ectoparasiticidal agents, has been achieved. Highlights of the effective modular synthetic strategy include anionic union of a tricyclic lactone with o-toluidine via our 2-substituted indole synthetic protocol, an optimized C-ring construction protocol, and a late-stage installation of the alpha,beta-unsaturated carboxylic acid side chain via the B-alkyl Suzuki-Miyaura cross-coupling tactic.
Asunto(s)
Diterpenos/síntesis química , Indoles/síntesis química , Insecticidas/síntesis química , Animales , Ciclización , Diterpenos/química , Diterpenos/farmacología , Indoles/química , Indoles/farmacología , Insecticidas/química , Insecticidas/farmacología , Estructura Molecular , Siphonaptera/efectos de los fármacos , EstereoisomerismoRESUMEN
[structure: see text] Construction of the heptacyclic core of (-)-nodulisporic acid D, a representative member of a recently discovered class of architecturally complex, ectoparasiticidal indole alkaloids, has been achieved. The modular synthetic strategy comprises an expedient, stereocontrolled synthesis of a tricyclic western hemisphere, in conjunction with union of an eastern hemisphere, exploiting the 2-substituted indole synthetic protocol introduced and developed in our laboratory.
Asunto(s)
Diterpenos/síntesis química , Indoles/química , Indoles/síntesis química , Diterpenos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The 1,2-addition of lithium phenylacetylide (PhCCLi) to quinazolinones was investigated using a combination of structural and rate studies. (6)Li, (13)C, and (19)F NMR spectroscopies show that deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with lithium hexamethyldisilazide affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi dimer. Although the mixed tetramer dominates at high mixed aggregate concentrations and low temperatures used for the structural studies, the mixed dimer is the dominant form at the low total mixed aggregate concentrations, high THF concentrations, and ambient temperatures used to investigate the 1,2-addition. Monitoring the reaction rates using (19)F NMR spectroscopy revealed a first-order dependence on mixed dimer, a zeroth-order dependence on THF, and a half-order dependence on the PhCCLi concentration. The rate law is consistent with the addition of a disolvated PhCCLi monomer to the mixed dimer. Investigation of the 1,2-addition of PhCCLi to an O-protected quinazolinone implicates reaction via trisolvated PhCCLi monomers.