1 The mechanisms underlying the vasodilator response to urocortin are incompletely understood. The present study was designed to examine the role of endothelial nitric oxide and Ba 2+ -sensitive K + channels in the endothelium-dependent component of urocortin-induced relaxation in the rat left anterior descending coronary artery. 2 Urocortin induced both endothelium-dependent and -independent relaxation with respective pD 2 of 8.64+0.03 and 7.90+0.10. Removal of endothelium reduced the relaxing potency of urocortin. In rings pretreated with 10 74 M N G -nitro-L-arginine methyl ester, 10 75 M methylene blue or 10 75 M ODQ, the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. L-Arginine (5610 74 M) antagonized the e ect of N G -nitro-L-arginine methyl ester. 3 The relaxant response to urocortin was reduced in endothelium-intact rings preconstricted by 3.5610 72 M K + and abolished when extracellular K + was raised to 5610 72 M. Pretreatment with 10 74 M BaCl 2 signi®cantly inhibited urocortin-induced relaxation. Combined treatment with 10 74 M BaCl 2 plus 10 74 M N G -nitro-L-arginine methyl ester did not cause further inhibition. In urocortin (10 78 M)-relaxed rings, BaCl 2 induced concentration-dependent reversal in vessel tone. Tertiapin-Q (10 76 M) also attenuated urocortin-induced relaxation. In contrast, BaCl 2 did not alter urocortininduced relaxation in endothelium-denuded rings. 4 In endothelium-denuded rings, hydroxylamine-and nitroprusside-induced relaxation was inhibited by 10 74 M BaCl 2 , but not by 10 76 M tertiapin-Q. 5 The endothelium of the coronary artery was moderately stained with the antiserum against urocortin. 6 Taken together, the present results indicate that the urocortin-induced endothelium-dependent relaxation of rat coronary arteries is likely attributable to endothelial nitric oxide and subsequent activation of Ba 2+ -or tertiapin-Q-sensitive K + channels. The urocortin-induced endotheliumdependent relaxation appears to be mediated by cyclic GMP-dependent mechanisms.
The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC 50 s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels.
Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.
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