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Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.

A series of optically active 1,1′-binaphthalene-derived receptors with N-(pyridine-2,6-diyl)acetamide [CONH(py)] H-bonding sites in the 6,6′-positions has been prepared for the enantioselective complexation of the N-carbobenzyloxy (Cbz)-protected excitatory amino acids aspartic (Asp) and glutamic (Glu) acid via two COOH· · ·CONH(py) H-bonding arrays and additional secondary bonding interactions. The conformational homogeneity of the receptors is enhanced by locking the dihedral angle θ about the chirality axis through the C(1)–C(1′) bond of the 1,1′-binaphthalene moiety either by bridging the 2,2′-positions or by attaching bulky substituents to these centres. Computer modelling has shown that bridging is more efficient in locking this dihedral angle than the introduction of bulky substituents, and these predictions have been confirmed by 1H NMR binding studies in CDCl3 and in CDCl3–CD3OD 99.8∶0.2. Plots of the enantioselectivity Δ(ΔG°) (difference in stability between diastereoisomeric complexes) in the recognition by the bridged receptors as a function of the enforced dihedral angle θ are peak-shaped, and the highest values have been measured in CDCl3 (300 K) for the complexation of the enantiomers of N-Cbz-Asp [Δ(ΔG°) = 6.9 kJ mol–1] and N-Cbz-Glu [Δ(ΔG°) = 5.2 kJ mol–1] by (R)-21 (θ = 86 ± 4°). The more stable diastereoisomeric complexes are highly structured, and tight host–guest bonding has been confirmed by the observation of up to five intermolecular NOEs. Enforcing the conformational homogeneity by bridging represents a new general principle for improving the chiral recognition potential of 1,1′-binaphthalene receptors.

The complexation of N-benzyloxycarbonyl (Cbz) derivatives of the excitatory amino acids L-aspartic acid (Asp; 1), L-glutamic acid (Glu; 3), and, for the first time, L-kainic acid ((2S,3S,3S)-2-carboxy-4-(1-methylethenyl)pyrrolidine-3-acetic acid; Kai; 5) was studied in CDCl3 with a diversity of chiral receptors consisting of a 1,1′-binaphthyl spacer with (carboxamido)pyridine (CONH(py)) functionality attached to the 6,6′-positions in the major groove. Receptors of type A possess two N-(pyridin-2-yl)carboxamide H-bonding sites (e.g.7), whereas type B-receptors have two N-(pyridine-6,2-diyl)acetamide residues attached (e.g.8 and 9). Complexes of excitatory amino-acid derivatives and other, achiral α,β-dicarboxylic acids with these receptors are primarily stabilized by two sets of CO···HN and OH ··· N H-bonds. Optically active type-A receptors such as (R)- and (S)-7 showed a preference for the larger Glu derivative, whereas type-B receptors such as (R)- and (S)-8 and (R)- and (S)-9 formed more stable complexes with the smaller Cbz-Asp. To improve the poor enantioselectivity shown by 7–9, additional functionality was introduced at the 7,7′-positions of the 1,1′-binaphthyl spacer, and the nature of the H-bonding sites in the 6,6′-positions was varied. Screening the diversity of new racemic receptors for binding affinity, which had been shown in many examples by Cram to correlate with enantioselectivity, demonstrated that (+)-10 and (+)-11 formed the most stable complexes with dicarboxylic acids, and these receptors were synthesized in enantiomerically pure form. Both are type-B binders and contain additional PhCH2O (10) and MeO (11) groups in the 7,7′-positions. By 1H-NMR binding titrations, the complexation of (R)- and (S)- 10 and (R)- and (S)-11 with the excitatory amino-acid derivatives was studied in CDCl3, and association constants Ka between 103 and 2 · 105 l mol−1 were measured for the 1:1 host-guest complexes formed. Whereas both 10 and 11 formed stable complexes, enantioselective binding was limited to the PhCH2O-substituted receptor 10, with the (R)-enantiomer complexing Cbz-Asp by 0.7 kcal mol−1 more tightly than the (S)-enantiomer. The structures of the diastereoisomeric complexes were analyzed in detail by experimental methods (complexation-induced changes in 1H-NMR chemical shifts, 1H{1H} nuclear Overhauser effect (NOE) difference spectroscopy) and computer modeling. These studies established that an unusual variety of interesting aromatic interactions and secondary electrostatic interactions are responsible for both the high binding affinity (ΔG° up to 7.2 kcal mol−1) and the enantioselection observed with (R)- and (S)-10. In an approach to enhance the enantioselectivity by reducing the conformational flexibility of the 1,1′-binaphthyl spacer, an additional crown-ether binding site was attached to the 2,2′-positions in the minor groove of the type-B receptors (R)- and (S)-48. Both the binding affinity and the enantioselectivity (Δ(ΔG°) up to 0.7 kcal mol−1) in the complexation of the excitatory amino-acid derivatives by (R)- and (S)-48 were not altered upon complexation of Hg(CN)2 at the crown-ether binding site, demonstrating lack of cooperativity between the minor- and major-groove recognition sites.

A variety of chiral 1,1'-binaphthyl derivatives with one or two hydroxyl groups at either the 2,2'-(minor groove) or the 7,7'-positions (major groove) were prepared for enantioselective recognition of the cinchona alkaloids quinine and quinidine. The study was initiated when it was found that (±)-7,7'-bis(benzyloxy)-2,2'-dihydrory-1,1'-binaphthyl ((±)-1a) was readily resolved through simple clathrate formation with quinine and quinidine. Optical resolution of (±)-1a was also achieved by fractional crystallization of its cyclic phosphate ester with quinidine. The absolute configuration of the optically pure binaphthyl derivatives was established by transformation of (-)-1a into a binaphthyl derivative of known absolute configuration (R) through reactions of defined stereochemistry. The X-ray crystal structure analysis of the (S)-(+)-1a.quinidine complex showed that ion pairing is the major interaction between the two components. Complexation of quinine and quinidine at both major and minor grooves of the 1,1'-binaphthyl derivatives occured in CDCl 3 with a significant degree of chiral recognition, and differences in stability between diastereomeric complexes were evaluated. Quinine is consistently better bound by the (R)-receptors whereas quinidine always prefers the (S)-enantiomers. The structures of the complexes, which are stabilized by hydrogen-bonding and aromatic-aromatic interactions, were analyzed on the basis of the complexation-induced changes in 1 H NMR chemical shifts of the binding partners at saturation binding, 1 H[ 1 H] nuclear Overhauser effects, and molecular modeling

Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P(1) receptor, we elucidate cellular and signaling mechanisms that are important in initiating cytokine storm. Whereas S1P(1) receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P(1) agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte-deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events that are both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P(1) signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases in which amplification of cytokine storm is a significant pathological component could be chemically tractable.

A novel series of 6,7-dihydro-4H-pyrazolo [1,5-a] pyrrolo [3,4-d] pyrimidine-5,8-dione inhibitors of the enzyme acyl-CoA: cholesterol O-acyltransferase is described. A number of these derivatives were found to obe potent modulators of serum lipoprotein levels in cholesterol-feld rats. Further evaluation of one of the most effective analogues confirmed that it was significantly blocking the absorption of cholesterol from the gut

Publisher Summary This chapter summarizes developments within the voltage-gated sodium channel (VGSC) field focusing on the structural classes. The nine VGSCs (NaV1.1–1.9) discovered to date are members of a larger voltage-gated ion channel super-family which regulates the electrical activity among cells and tissues, and is involved in many physiological processes such as cognition, locomotion, and nociception. Of the nine VGSCs, NaV1.1, NaV1.2, NaV1.3, and NaV1.6 are distributed throughout the central nervous system (CNS). NaV1.4 is present in muscle tissue, and NaV1.5 is in cardiac myocytes, while NaV1.7, NaV1.8, and NaV1.9 are distributed in the peripheral nervous system (PNS). It is now known, however, that the expression of VGSCs can change significantly under pathological conditions such as neuropathic pain or multiple sclerosis (MS). For example, NaV1.8 mRNA and protein are up-regulated within cerebellar purkinje cells in animal models of MS and in human MS conditions. Similarly, mRNA for NaV1.8 is down-regulated in the dorsal root ganglia (DRG) but up-regulated in undamaged neurons in both rodent models of neuropathic pain and in human chronic pain conditions. The attention derived from the recent genetic studies of loss-of-function mutations of SCN9A (NaV1.7) in man has propelled these targets to the forefront of drug discovery.

The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.

Publisher Summary This chapter examines the different aspects of selective androgen receptor modulators (SARMS). Testosterone (T) is an endogenous ligand for the androgen receptor (AR) and is essential for the development and maintenance of the male reproductive system and secondary male sex characteristics. SARMs with agonist activity in most target tissues but the prostate and other SARMs with antagonist activity only in prostate are likely to fulfill important unmet medical needs for a growing aging population. The discovery and development of SARMs can provide tissue-specific molecules for a specific indication. The therapeutic potential of SARMs should be expanded beyond the current androgen applications with better or total separation of the anabolic and androgenic activities of androgens. The AR is expressed in rat neurons and 5α- dihydrotestosterone upregulates neural AR in mice and rats. In the hamster, androgen was found to affect neural development in the hypothalamus and amygdala. A study reported that androgens at pharmacological doses increased serum erythropoietin (EPO) levels in anemic patients with non-severe aplastic anemia and myelodysplastic syndromes but not in non-anemic patients.

A novel series of 6,7-dihydro-4H-pyrazolo [1,5-a] pyrrolo [3,4-d] pyrimidine-5,8-dione inhibitors of the enzyme acyl-CoA: cholesterol O-acyltransferase is described. A number of these derivatives were found to obe potent modulators of serum lipoprotein levels in cholesterol-feld rats. Further evaluation of one of the most effective analogues confirmed that it was significantly blocking the absorption of cholesterol from the gut

Cycloaddition of β-alkyl- or β-arylenones to bicyclic sydnone 3 in the absence of added oxidant affords mixtures of the tetrahydropyrazolo[1,5-a]pyridines 4 and 5 . The amount of 5 formed was dependent on the nature of R.

Cycloaddition of β-alkyl- or β-arylenones to bicyclic sydnone 3 in the absence of added oxidant affords mixtures of the tetrahydropyrazolo[1,5-a]pyridines 4 and 5 . The amount of 5 formed was dependent on the nature of R.