High-throughput cell-based techniques that permit early detection of compound-induced genotoxic damage have recently become available. Methods based on induction of the GADD45a promoter are attractive because multiple intracellular mechanisms that detect genetic damage intersect at this checkpoint gene. Consequently, assays such as GreenScreen HC, which uses p53-competant human TK6 lymphoblastoid cells and a GADD45a-GFP reporter, have been developed. GreenScreen HC allows weekly testing of dozens of compounds using 96-well microplates, with high interassay consistency. BlueScreen HC is a recent advancement, coupling GADD45a to Gaussia luciferase, with several advantages over GADD45a-GFP including the potential for miniaturization. Here we describe implementation of a 384-well BlueScreen assay. For drug discovery programs carrying out iterative analogue synthesis around a chemical lead series, these assays permit assessment of compound genotoxic potential in parallel to, rather than subsequent to, determination of activity at a therapeutic target. We demonstrate comparability of BlueScreen-384 to GreenScreen HC and illustrate the use of BlueScreen-384 to explore the structure-activity relationship around a genotoxic lead molecule to identify nongenotoxic analogues. BlueScreen-384 can reduce the need for costly and time-consuming analogue testing in more traditional genotoxicity tests, such as the Ames test.

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A synthesis of the macrocyclic core structure of callipeltoside A and a C9 epimer has been achieved by applications of chiral vinylzinc or Kishi-Nozaki-Hiyama (K-N-H) additions, Roskamp homologations, and acylketene or intramolecular K-N-H macrolactonizations as key bondforming steps.

Conjugated aldehydes undergo smooth Pd(OAc)2.PPh3- or Me2CuCNLi2-catalyzed 1,4-addition of dialkylzinc reagents. [reaction: see text].

A convenient route to the enantiomers of 4-TIPS-3-butyn-2-ol of >95% enantiomeric purity by reduction of the ynone precursor 4 with the Noyori N-tosyl-1,2-diphenylethylenediamineruthenium cymene catalyst is described. The mesylate derivative of the (S) enantiomer (1c) is converted in situ to an allenylzinc or indium reagent in the presence of a catalyst derived from Pd(OAc)2 and Ph3P and either Et2Zn or InI. A second in situ addition of these reagents to aldehydes leads to anti homopropargylic alcohol adducts. The additions proceed in generally high (60-90%) yield with modest to excellent diastereoselectivity and high enantioselectivity. Only slight mismatching (<5%) is observed with chiral alpha-methyl and alpha-silyloxy aldehydes. Additions to alpha-substituted enals are highly diastereoselective, while beta,beta-disubstituted enals afford ca. 2:1 mixtures of anti and syn adducts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

[reaction: see text] Additions of vinylic zinc bromide reagents to alpha-chiral aldehydes (R(1) = CH(2)OTBS, R(2) = Me; R(1) = Me, R(2) = OTBS) in the presence of lithiated (+)- or (-)-N-methylephedrine proceed with predominant reagent control to afford anti or syn adducts stereoselectively, except when the aldehydes possess an alkoxy substituent at the alpha- or beta-positions (R(1) = Me, R(2) = OBn; R(1) = CH(2)OBn, R(2) = Me), in which case chelation-controlled adducts predominate.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.