The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the ...sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.
The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context ...of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.
This article presents a stereospecific scale-up synthesis of (S)-1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic ...acid (BMS-960), a potent and selective isoxazole-containing S1P1 receptor agonist. The process highlights an enzymatic reduction of α-bromoketone toward the preparation of (S)-bromo alcohol, a key precursor of (S)-4-(oxiran-2-yl)benzonitrile. A regioselective and stereospecific epoxide ring-opening reaction was also optimized along with improvements to 1,2,4-oxadiazole formation, hydrolysis, and crystallization. The improved process was utilized to synthesize batches of BMS-960 for Ames testing and other toxicological studies.
The mechanism(s) for post-bed rest (BR) orthostatic intolerance is equivocal. The vestibulosympathetic reflex contributes to postural blood pressure regulation. It was hypothesized that muscle ...sympathetic nerve responses to otolith stimulation would be attenuated by prolonged head-down BR. Arterial blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), and peripheral vascular conductance were measured during head-down rotation (HDR; otolith organ stimulation) in the prone posture before and after short-duration (24 h; n = 22) and prolonged (36 ± 1 day; n = 8) BR. Head-up tilt at 80° was performed to assess orthostatic tolerance. After short-duration BR, MSNA responses to HDR were preserved (Δ5 ± 1 bursts/min, Δ53 ± 13% burst frequency, Δ65 ± 13% total activity; P < 0.001). After prolonged BR, MSNA responses to HDR were attenuated ∼50%. MSNA increased by Δ8 ± 2 vs. Δ3 ± 2 bursts/min and Δ83 ± 12 vs. Δ34 ± 22% total activity during HDR before and after prolonged BR, respectively. Moreover, these results were observed in three subjects tested again after 75 ± 1 days of BR. This reduction in MSNA responses to otolith organ stimulation at 5 wk occurred with reductions in head-up tilt duration. These results indicate that prolonged BR (∼5 wk) unlike short-term BR (24 h) attenuates the vestibulosympathetic reflex and possibly contributes to orthostatic intolerance following BR in humans. These results suggest a novel mechanism in the development of orthostatic intolerance in humans.
This article reports an efficient scale-up synthesis of 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (BMS-520), a potent and ...selective isoxazole-containing S1P1 receptor agonist. This process features a highly regioselective cycloaddition leading to a key intermediate, ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate, a chemo-selective hydrolysis of its regioisomers, as well as an improved method for 1,2,4-oxadiazole formation, relative to the original synthesis. The improved process was applied to the preparation of multiple batches of BMS-520 for preclinical toxicological studies.
Studies on the stereo- and regioselectivity of rhodium(I)-catalyzed 5 + 2 cycloadditions of 2-substituted-1-vinylcyclopropanes are described. The relative stereochemistry of vicinal cyclopropane ...substituents is found to be conserved in these reactions, translating into distinct 1,4- or 1,5-stereorelationships in the cycloadducts. Exceptional regioselectivity in cyclopropane bond cleavage and even reversal of cleavage selectivity can be obtained through judicious selection of substituents and/or catalyst.
Penn State Heart and Vascular Institute, Department of Cellular and Molecular Physiology, General Clinical Research Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
...Submitted 22 May 2007
; accepted in final form 3 July 2007
Activation of the vestibular otolith organs with head-down rotation (HDR) increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26 ± 1 yr) performed three trials of HDR to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8–1.0 µg·kg –1 ·min –1 ), and phenylephrine (baroreflex loading: 0.6–0.8 µg·kg –1 ·min –1 ) infusion. Nitroprusside infusion decreased ( 7 ± 1 mmHg, where is change; P < 0.001) and phenylephrine infusion increased mean arterial pressure ( 8 ± 1 mmHg; P < 0.001) at rest. HDR performed during the control 3 ± 2 bursts/min, 314 ± 154 arbitrary units (au) total activity, 41 ± 18% total activity; P < 0.05 and nitroprusside trials 5 ± 2 bursts/min, 713 ± 241 au total activity, 49 ± 20% total activity; P < 0.05 increased MSNA similarly despite significantly elevated levels at rest (13 ± 2 to 26 ± 3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA ( 0 ± 1 bursts/min, –15 ± 33 au total activity, –8 ± 21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.
autonomic nervous system; blood pressure; orthostasis; sympathetic nerve activity
Address for reprint requests and other correspondence: C. A. Ray, Heart & Vascular Institute H047, Penn State College of Medicine, 500 Univ. Dr., Hershey, PA 17033-2390 (e-mail: caray{at}psu.edu )
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Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central ...pyridyl based analogs 2–4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.
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