RESUMEN
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 strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
RESUMEN
An efficient, stereoselective synthesis of 4'-Ed4T is demonstrated. The synthesis is highlighted by a regioselective TMSOTf-mediated acetal opening, a Claisen rearrangement to set the key 4'-stereocenter as well as the olefin, and a one-pot nonaflation/elimination to deliver the alkyne moiety. The synthesis proceeds in eight steps from 5-methyluridine and occurs in 37% overall yield.
Asunto(s)
Estavudina/análogos & derivados , Uridina/análogos & derivados , Alquenos/química , Alquinos/química , Estructura Molecular , Estavudina/síntesis química , Estavudina/química , Estereoisomerismo , Uridina/síntesis química , Uridina/químicaRESUMEN
The effects of natural and synthetic eicosanoids on the diameter of rat interlobular arteries studied in vitro were compared to that of the potent, endogenous vasoconstrictor 20-HETE. Vasoconstrictor activity was optimum for chain lengths of 20-22 carbons with at least one olefin or epoxide between located between C(13)-C(15) and an oxygen substituent at C(20)-C(22). The presence of delta (Zou et al. Am. J. Physiol. 1996, 270, R228; Gebremedhin, D. et al. Am. J. Physiol. 1998, 507, 771)-, delta (Carroll et al. Am. J. Physiol. 1996, 271, R863; Vazquez et al. Life Sci. 1995, 56, 1455)-, or delta (Imig et al. Hypertension 2000, 35, 307; Lopez et al. Amer. J. Physiol. 2001, 281, F420)-olefins had no influence on the vasoconstrictor response whereas the introduction of a C(7)-thiomethylene enhanced potency. A sulfonamide or alcohol, but not a lactone, could replace the C(1)-carboxylate. These data were used to construct a putative binding domain map of the 20-HETE receptor consisting of: (i) a comparatively open, hydrophilic binding site accommodating the C(1)-functionality; (ii) a hydrophobic trough spanning the olefins; (iii) a shallow pocket containing a critical pi-pi binding site in the vicinity of the pi (Ito et al. Am. J. Physiol. 1998, 274, F395; Quigley, R.; Baum, M.; Reddy, K. M.; Griener, J. C.; Falck, J. R. Am. J. Physiol. 2000, 278, F949)-olefin; and (iv) an oxyphilic binding site proximate to the omega-terminus.