The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

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This report discloses the discovery and characterization of imidazo [1,2-a]pyrazines and pyrazolo-[1,5-c]pyrimidines as selective negative modulators of αamino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure−activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 exhibited time-and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

A new stereospecific synthesis of phospholipid derivatives of 1,2-diacyl-sn-glycerols is reported. The synthesis is based on (1) the use of L-glyceric acid as the stereocenter for construction of the optically active phospholipid molecule, (2) preparation of 3-triphenylmethyl-sn-glycerol as the key intermediate for sequential introduction of the primary and secondary acyl functions leading to the chiral diglycerides, and (3) elaboration of the sn-3-phosphodiester headgroup via phosphorylation using 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by ring opening of the five-membered phosphorus heterocycle with trimethylamine, ammonia, as well as oxygen and sulfur nucleophiles. The sequence has been shown to be suitable for the preparation of both symmetric and mixedchain diacylglycerols with saturated and unsaturated acyl substituents. Phospholipid headgroups including phosphocholine, phosphoethanolamine, phosphoethanol, and phosphoethylthioacetate functions have been prepared. Application of the method to the synthesis of functionalized phosphatidylcholines has also been demonstrated by incorporating spectroscopically active spinlabeled and fluorescent reporter groups via postsynthetic derivatization of chain terminal ω-aminoalkyl functions of the acyl substituents of the compounds. The synthetic methods developed have a great deal of flexibility, providing convenient routes to a wide range of structurally variable phospholipids for physicochemical, enzymological, and cell-biological studies.The development of new synthetic methods for the preparation of structurally well-defined phospholipid compounds has become a timely and important goal since it was discovered that in addition to their role as a major component in all biological membranes 1,2 phospholipids are also involved in a wide range of physiological and regulatory processes. 3-12 Phospholipids are essential for the functioning of a number of membrane-bound enzymes such as protein kinase C 5,10,11 and play an important role in signal transduction 4-6 as substrates for the production of second messengers 5,12 (inositol-1,4,5-trisphophate, diacylglycerol) and in the release of arachidonic acid. Significantly, some of the most potent phospholipid compounds, which are active below the micromolar 8 and nanomolar 3 levels, occur in low concentrations in the cell, such that preparation of synthetic derivatives represents a clear prerequisite to elucidation of their biochemical mechanism of action. The compounds are required for both structural and dynamic studies of biomembranes 13-16 and membrane-bound enzymes, 5,10,11,17 with particular emphasis on establishing structure-activity relationships with respect to phospholipid-phospholipid 13-16 and phospholipid-protein 17 interactions. Furthermore, delineation of the structural requirements for the biological activities of phospholipids will not only advance the current level of understanding of the chemistry and biology of these compounds but also provide important insight into the design of new target molec...

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