Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

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.

rings with 7 or more members rings with 7 or more members Q 0050 -085Radical Cation-Mediated Annulation. Stereoselective Construction of Bicyclo[5.3.0]decan-3-ones by Aerobic Oxidation of Cyclopropylamines.-Intramolecular Kulinkovich cyclopropanation of olefin-tethered amides such as (I) and (VII) followed by tandem ring expansion-cyclization of the resulting bicyclic aminocyclopropenes offers a stereocontrolled method to prepare bicyclo[5.3.0]decan-3-ones.

[formula: see text] A new approach to a suitably functionalized tricyclic core of sarains has been developed by means of Katritzky's cycloaddition using 3-oxidopyridinium betaines. A key step was the regioselective differentiation of the two nearly identical hydroxy groups derived from oxidative cleavage of the double bond in 8 to afford 14. A stereocontrolled construction of the tricyclic core 20 of sarains containing the requisite side chain at C-3' was achieved by an intramolecular conjugate addition.

High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented. KEYWORDS: DGAT1, triglyceride synthesis, efflux O rally ingested triglycerides (TG) undergo hydrolysis and then are reassembled within enterocytes into TG-rich chylomicrons destined for systemic circulation. The final committed step in triglyceride biosynthesis is known to be mediated by at least two distinct intracellular acyl-coA diacylglycerol acyltransferases (DGATs), namely DGAT1 1 and DGAT2. 2 Since the development of whole-body knockout models of these enzymes, there has been intense evaluation of pharmacological approaches to modulate their activity. 3−8 For DGAT1, this interest is inspired by the favorable metabolic phenotype of DGAT1 −/− mice, 9 which are resistant to dietinduced body weight gain, 10 are more insulin-sensitive relative to wild-type littermates, 11 and exhibit a reduced rate of chylomicrons formation when challenged with lipid nutrients. 12 Interestingly, all aspects of this phenotype are lost when DGAT1 is reintroduced via a tissue-specific promoter into the intestines of female DGAT1 −/− mice, implying that intestinal DGAT1 plays a crucial role in the effects observed in the whole-body knockout model. 13 Indeed, DGAT1 mRNA expression levels have been shown to be high in regions of the small intestine in mice and humans. 14,15 Selective inhibition of intestinal DGAT1 therefore becomes an intriguing drug discovery approach to recapitulate aspects of the DGAT1 −/− mouse, especially if this gut-specific inhibition reduces the potential risk of on-and off-target activity for candidate molecules. Particularly relevant for DGAT1 pharmacological inhibition is the observation of functional and morphological abnormalities in the fur and sebaceous glands of DGAT1 −/− mice. 16 In this report we describe a novel approach to specifically inhibit intestinal DGAT1, and demonstrate the potential viability of this strategy with regard to efficacy and safety in multiple preclinical models.High-throughput screening efforts using recombinant human DGAT1 enzyme identified the benzimidazole 1 (DGAT1 IC 50 = 1.3 μM; DGAT2 IC 50 > 20 μM; Figure 1) as a potential starting point for optimization. Initial structural modifications demonstrated that both the ethyl carbamate and the 2,6-dichlorophenyl substituents on the benzimidazole core could be replaced without substantial loss of activity (i.e., 2, DGAT1 IC 50 = 1.4 μM), and in fact introducing an additional substituent at the 4-position of the 2,6-dimethylphenyl ring led to an im...

A convenient approach to the synthetically challenging tricyclic core of gelsemine (1) has been developed by the titaniummediated intramolecular coupling of bicyclic w-vinylimides.

[reaction: see text] In connection with the known diyne-ene [2 + 2 + 2] cycloaddition reactions mediated by titanium aryloxides, the ability of titanium alkoxides to promote coupling of a titanacyclopentadiene with an alkene has been assessed for the isomerization-free preparation of 1,3-cyclohexadienes. The successful cycloaddition by titanium alkoxides is predicated on the use of homoallylic alcohols as the olefin component. With secondary homoallylic alcohols, high 1,3-diastereoselectivity is observed, which lends itself to enantioselective preparation of functionalized 1,3-cyclohexadienes.

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