The remarkable binding properties of serum albumin have been investigated extensively, but little is known about an important class of fatty acids, the very longchain saturated fatty acids (VLCFA; Ͼ 18 carbons). Although VLCFA are metabolized efficiently in normal individuals, they are markers for and possibly causative agents of several peroxisomal disorders. We studied the binding of

The synthesis of the O-vinyl ether phospholipid plasmalogen 1 from 2,3-bis-O-[p-methoxybenzyl (PMB)]-sn-glycerol (13) is described. Treatment of 13 with potassium hydride, trichloroethylene, and n-butyllithium gave a 1-O-alkynyl glycerol derivative, which was alkylated with 1-iodohexadecane to afford the long-chain O-alkynyl ether 14. The latter was quantitatively converted to cis-enol ether 15 (Z/E ratio between 35:1 and 100:1) with Lindlar catalyst in hexane/EtOAc 1:1 containing quinoline. The PMB groups of 15 were removed by Birch reduction (Na, NH3), giving 1-O-[1‘-(Z)-octadecenyl]-sn-glycerol (2) in 95% yield. Regioselective silylation of 2 followed by palmitoylation provided 1-O-[1‘-(Z)-octadecenyl]-2-O-palmitoyl-3-(tert-butyldiphenylsilyl)-sn-glycerol (17). Desilylation with Bu4NF/imidazole at −23 °C followed by phosphocholine insertion (using 2-chloro-2-oxo-1,3,2-dioxaphospholane with 2 equiv of pyridine in benzene at 4 °C and then trimethylamine in benzene/MeCN 1:3 at 70 °C) completes the synthesis of plasmalogen (1).

No abstract

bGSK1322322 is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (n ‫؍‬ 2,370), Moraxella catarrhalis (n ‫؍‬ 115), Streptococcus pneumoniae (n ‫؍‬ 947), Streptococcus pyogenes (n ‫؍‬ 617), and Staphylococcus aureus (n ‫؍‬ 940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC 90 of 1 g/ml against M. catarrhalis and 4 g/ml against H. influenzae, with 88.8% of ␤-lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by <4 g/ml of GSK1322322, with an MIC 90 of 2 g/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC 90 of 1 g/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains, with an MIC 90 of 0.5 g/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC 90 of 4 g/ml in all cases. Time-kill studies showed that GSK1322322 had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a >3-log 10 decrease in the number of CFU/ml at 4؋ MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK1322322 represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens.

Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)--(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC of 0.3 nM and is efficacious .