Lin Chu

Initial structure–activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-arylindoles

A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.

Synthesis of 2-aryltryptamines with palladium catalyzed cross-coupling of 2-bromotryptamines and arylboronic acids

Abstract A versatile and high-yielding synthesis of 2-aryltryptamines employing palladium(0) catalyzed cross-coupling of 2-bromotryptamines and arylboronic acids was developed. The preparation of the intermediate 2-bromotryptamines with pyridine hydrobromide perbromide as the brominating agent, is also reported.

SAR studies of novel 5-substituted 2-arylindoles as nonpeptidyl GnRH receptor antagonists

The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported.

Expression, purification and crystallization of human 5-lipoxygenase-activating protein with leukotriene-biosynthesis inhibitors

The nuclear membrane protein 5-lipoxygenase-activating protein (FLAP) plays an essential role in leukotriene synthesis. Recombinant full-length human FLAP with a C-terminal hexahistidine tag has been expressed and purified from the cytoplasmic membrane of Escherichia coli. Diffraction-quality crystals of FLAP in complex with leukotriene-synthesis inhibitor MK-591 and with an iodinated analogue of MK-591 have been grown using the sitting-drop vapor-diffusion method. The crystals exhibit tetragonal symmetry (P42(1)2) and diffracted to a resolution limit of 4 A.

Aliphatic replacements of the biphenyl moiety of the nonpeptidyl growth hormone secretagogues L-692,429 and L-692,585

Abstract Replacement of the central phenyl ring of the biphenyl moiety in the novel growth hormone (GH) secretagogues L-692,429 and L-692,585 with partially or completely saturated surrogates has been investigated. The cyclohexenyl analogue 37 displayed GH releasing activity comparable to L-692,585, indicating that the aromaticity of this central ring is not critical for bioactivity and that this ring may serve primarily to orient the benzolactam and phenyltetrazole pharmacophores.

Evaluation of endo- and exo-aryl-substitutions and central scaffold modifications on diphenyl substituted alkanes as 5-lipoxygenase activating protein inhibitors.

A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.