X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone ...but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.
The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate ...further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template Palczewski, K., et al. (2000) Science 289, 739-745. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644.
The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant
1 are described. The initial inspiration for these ...taranabant derivatives was its conformation
1a, determined by
1H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure.
The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant
1 are described. The initial inspiration for these taranabant derivatives was its conformation
1a, determined by
1H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of
1 to a homology model of CB1R.
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that ...activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.
We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, ...where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that ...activates p38 and c-Jun N-terminal kinase (JNK) mitogenactivated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.
The oxazolidinone 2 derived from amino indanol 1 functions as a very efficient chiral auxiliary for the Diels-Alder reaction. The effect of conformation has been explored using a range of constrained ...phenyl glycinol analogues.
The in vitro biological characterization of a series of 4-(alkylamino)-1,4-dihydroquinolines is reported. These compounds are novel inhibitors of voltage-activated n-type potassium ion (K+) channels ...in human T lymphocytes. This series, identified from random screening, was found to inhibit 125Icharybdotoxin binding to n-type K+ channels with IC50 values ranging from 10(-6) to 10(-8) M. These analogs also inhibit whole cell n-type K+ currents with IC50 values from 10(-5) to 10(-7) M. The preparation of a series of new 4-(alkylamino)-1,4-dihydroquinolines is described. Structure-activity relationships are discussed. Naphthyl analog 7c, the best compound prepared, exhibited > 100-fold selectivity for inhibition of 125Icharybdotoxin binding to n-type K+ channels compared with inhibition of 3Hdofetilide binding to cardiac K+ channels. These compounds represent a potent and selective series of n-type K+ channel inhibitors that have the potential for further development as anti-inflammatory agents.
Correolide (
1) was converted to a new series of tetracyclic Kv1.3 blockers
2. SAR for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein.
...Kv1.3, the voltage-gated potassium channel in human T cells, represents a new target for treating immunosuppression and autoimmune diseases. Correolide (
1), a pentacyclic natural product, is a potent and selective Kv1.3 channel blocker. Simplification of correolide via removal of its E-ring generates enone
4, whose modification produced a new series of tetracyclic Kv1.3 blockers. The structure–activity relationship for this class of compounds in two functional assays, Rb_Kv and human T cell proliferation, is presented herein. The most potent analog
43 is 15-fold more potent than correolide as inhibitor of human T cell proliferation.
Structure–activity relationship studies directed toward the optimization of (2
S)-2-(3-chlorophenyl)-1-
N-(methyl)-
N-(phenylsulfonyl)amino-4-4-(substituted)piperidin-1-ylbutanes as CCR5 antagonists ...resulted in the synthesis of the spiro-indanone derivative
8c (IC
50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.
Structure–activity relationship studies directed toward the optimization of (2
S)-2-(3-chlorophenyl)-1-
N-(methyl)-
N-(phenylsulfonyl)amino-4-4-(substituted)piperidin-1-ylbutanes as CCR5 antagonists resulted in the synthesis of the spiro-indanone derivative
8c (IC
50=5 nM). These and previous results are summarized in a proposed pharmacophore model for this class of CCR5 antagonist.
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