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Illek, Beate, Mike E. Lizarzaburu, Vivien Lee, Michael H. Nantz, Mark J. Kurth, and Horst Fischer. Structural determinants for activation and block of CFTR-mediated chloride currents by apigenin. Am J Physiol Cell Physiol 279: C1838-C1846, 2000.--Apigenin (4',5,7-trihydroxyflavone) is an activator of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated [Cl.sup.-] currents across epithelia at low concentrations and a blocker at high concentrations. We determined the roles of structural components of apigenin for both stimulation and block of [Cl.sup.-] currents across Calu-3 epithelia. The half-maximal binding affinity of apigenin for current stimulation ([K.sub.s]) was 9.1 [+ or -] 1.3 [micro]M, and the rank-order of molecular structures was 7-hydroxyl [is greater than] pyrone = 4'-hydroxyl [is greater than] 5-hydroxyl. Both the 7-hydroxyl and the 4'-hydroxyl served as H-bond acceptors, whereas the 5-hydroxyl was an H-bond donor. The half-maximal binding affinity of apigenin during current block was 74 [+ or -] 11 [micro]M. Blocked [Cl.sup.-] currents were structurally determined by 7-hydroxyl = 4'-hydroxyl [is greater than] pyrone [is greater than] 5-hydroxyl. Prestimulation of tissues with forskolin significantly affected activation kinetics and binding characteristics. After forskolin stimulation, [K.sub.s] was 4.1 [+ or -] 0.9 [micro]M, which was structurally determined by pyrone [is greater than] all hydroxyls [is greater than] single hydroxyls. In contrast, block of [Cl.sup.-] current by apigenin was not affected by forskolin stimulation. We conclude that apigenin binds to a stimulatory and an inhibitory binding site, which are distinguished by their affinities and the molecular interactions during binding. flavonoids; resveratrol; binding site; chloride transport; epithelia; cystic fibrosis transmembrane conductance regulator

Abstract: The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described. [Copyright &y& Elsevier]

Abstract: Previous efforts have led to the identification of a potent, selective, and nonphlorizin based SGLT2 inhibitor 1. This Letter describes efforts to further optimize the potency, microsomal stability, solubility and pharmacokinetic properties of this series of SGLT2 inhibitors. From these efforts, compounds 28 and 32 have improved solubility and pharmacokinetic properties compared to compound 1 [Copyright &y& Elsevier]

Abstract: Piperazine-bisamide analogs were discovered as partial agonists of human growth hormone secretagogue receptor (GHSR) in a high throughput screen. The partial agonists were optimized for potency and converted into antagonists through structure–activity relationship (SAR) studies. The efforts also led to the identification of potent antagonist with favorable PK profile suitable as a tool compound for in vivo studies. [Copyright &y& Elsevier]

The design and parallel synthesis of potent, small molecule partial agonists of Neuromedin B receptor based on the 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide core is described. [Copyright &y& Elsevier]

A four-step synthesis to aryl ether derivatives, three of which utilize polymer-supported reagents, has been developed. Supported triphenylphosphine was successfully utilized in two distinct synthetic processes in the first step, whilst supported base and ionic and covalent scavengers were employed to complete the synthesis and purification of the target compounds. [Copyright &y& Elsevier]

A series of dialkyl-[2-(3-alkylsulfanylmethyl-1H-indol-2-yl)-ethyl]amines was produced using a novel route involving nucleophilic ring opening of 2,2-dialkyl-1,2,3,4-tetrahydro-γ-carbolinium salts with thiols. The insertion reaction was mediated by a strong, polymer-supported base, and the purification of the target compounds was facilitated using resin-bound sulfonic acid. [Copyright &y& Elsevier]

Optimum conditions for the preparation of aryl–alkyl ethers from N-protected aminoalcohols using polymer-supported triphenylphosphine have been developed. In contrast to previous literature reports, it was discovered that the progress of this reaction is greatly improved when a tertiary amine base is employed, along with minor modifications being made to the order of reagent addition. [Copyright &y& Elsevier]

Abstract: A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca2+ concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties. [Copyright &y& Elsevier]

Abstract: GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels. [Copyright &y& Elsevier]