RESUMO
The four stereoisomers of the endothelial-derived vasorelaxant 11,12,15(S)-trihydroxyeicosatrienoic acid [1, 11,12,15(S)-THETA] were prepared by a triply convergent, asymmetric route that exploited the stereospecific, copper mediated cross-coupling of alpha,beta-dialkoxystannanes with organic electrophiles and the utility of dialkylthionocarbamates as orthogonal alcohol protective groups. Only 11(R),12(S),15(S)-THETA was comparable to natural material by HPLC, GC/MS, and in vitro bioassay.
Assuntos
Ácidos Eicosanoicos/síntese química , Endotélio Vascular/metabolismo , Vasodilatadores/síntese química , Cromatografia Líquida de Alta Pressão , Ácidos Eicosanoicos/química , Cromatografia Gasosa-Espectrometria de Massas , Estereoisomerismo , Vasodilatadores/químicaRESUMO
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.
Assuntos
Ácidos Hidroxieicosatetraenoicos/síntese química , Ácidos Hidroxieicosatetraenoicos/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Sítios de Ligação , Rim/irrigação sanguínea , Espectroscopia de Ressonância Magnética , Ratos , Receptores Eicosanoides/química , Relação Estrutura-AtividadeRESUMO
Investigations on P(2)-P(3)-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P(1)-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P(1)-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines.
Assuntos
Antitrombinas/química , Antitrombinas/farmacologia , Arginina/química , Compostos Heterocíclicos/química , Animais , Antitrombinas/síntese química , Cães , Relação Estrutura-AtividadeRESUMO
Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa approximately non-basic-8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.