Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.     

Cyclic urea derivatives as potent NK1 selective antagonists

A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.     

Facile synthesis of high affinity styrylpyridine systems as inherently fluorescent ligands for the estrogen receptor

A series of styrylpyridine derivatives containing two phenols was prepared via an efficient two-step synthesis. These compounds were designed to maximize the estrogen receptor binding affinity of a known series of inherently fluorescent styrylpyridines. While significant improvements were achieved in receptor affinity, the fluorescence intensity of this series of compounds is poor.     

Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors

A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.     

Synthesis, structure-affinity relationships, and molecular modeling studies of novel pyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists

This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c]quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A(1) and A(2A) AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA(1) subtype. To rationalize the observed structure-affinity relationships, molecular docking studies at A(2A)AR-based homology models of the A(1) and A(3) ARs and at the A(2A)AR crystal structure were carried out.     

Nonpeptide alpha V beta 3 antagonists. Part 9: Improved pharmacokinetic profile through the use of an aliphatic, des-amide backbone

A series of alphaVbeta3 receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.     

Synthesis and biological evaluation of C-12' substituted vinflunine derivatives

A series of novel C-12' substituted vinflunine derivatives have been synthesized. Several compounds in this series possess comparable in vitro cytotoxic potency against A549 cell lines.     

Agonist lead identification for the high affinity niacin receptor GPR109a

A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.     

Inhibitors of NF-kappaB derived from thalidomide

A series of compounds originally derived from thalidomide were synthesized and evaluated. The most potent compounds in this series, 5HPP-33 and compound 20, inhibited NF-kappaB activation in HeLa cells. Preliminary study indicated that the mechanism of inhibition of NF-kappaB activation is through inhibition of its translocation from the cytoplasm to the nucleus.     

Synthesis and antibacterial activity of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives

A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.     

Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors

We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).     

Cyclobutane derivatives as potent NK1 selective antagonists

A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki 相似文献   

Novel class of bivalent glutathione S-transferase inhibitors

Exploiting the principle of bivalent binding, we have designed symmetrical, bifunctional inhibitors to simultaneously occupy both active sites of cytosolic glutathione S-transferase, with enhanced specificity for the P1-1 isoform. We have prepared two series of compounds that differ in their binding domains-the first is a series of bis-glutathione conjugates, and the second is a series of compounds each possessing two equivalents of Uniblue A, an analogue of Cibacron Blue. For each series, a monofunctional reference compound was also prepared to determine the relative advantage of the bivalent inhibitors. Within each series, the most potent inhibitors exhibited IC(50) values 2 orders of magnitude lower than the relevant reference compounds. Moreover, within the bis-glutathionyl series, a 10-fold increase in selectivity was achieved for GST P1-1 over the A1-1 isoform. Isothermal titration calorimetry with a representative bis-glutathione conjugate and a monofunctional reference compound indicates that the bivalent inhibitor exhibits the expected increase in intrinsic affinity and decrease in stoichiometry relative to the monofunctional compound, supporting the overall design strategy.     

Novel coumarin derivatives as potential antidyslipidemic agents

A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.     

Design and synthesis of tricyclic sulfones as γ-secretase inhibitors with greatly reduced Notch toxicity

A novel series of tricyclic γ-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous γ-secretase inhibitors.     

Synthesis of 3-benzyl-2-substituted quinoxalines as novel monoamine oxidase A inhibitors

A new series of 3-benzyl-2-substituted quinoxalines have been synthesized by means of microwave enhancement of nucleophilic substitution reaction involving the corresponding 2-chloroquinoxaline analogs and substituted amines or hydrazine. The synthesized compounds were evaluated for their monoamine oxidase A and B inhibitory activity by determination of their IC(50). All the newly synthesized compounds showed more selective inhibitory activity toward MAO-A than MAO-B. In addition, the acute toxicity of the synthesized compounds was determined. This work may be a fruitful matrix of the synthesis of a new series of novel MAO-A inhibitors with good safety margins.     

A QSAR study on some series of anti-hepatitis B virus (HBV) agents

A quantitative structure-activity relationship (QSAR) study has been made on some series of anti-hepatitis B virus (HBV) agents, namely, a series of novel bis(L-amino acid) ester prodrugs of 9-[2--(phosphonomethoxy)ethyl]adenine, a similar series of compounds comprising of 2- amino-6-arylthio-9-[2-(phosphonoethoxy)ethyl] purine bis(2,2,2- trifluoroethyl) esters, and a series of 1-isopropylsulfonyl-2-amine benzimidazoles. In each case significant correlations are found between the anti-HBV potencies and some physicochemical and steric properties of the compounds, indicating that for the first two series the activity is controlled by the hydrophobic and the bulk properties of the molecules and, for the third series, the steric and hydrogen bonding properties of compounds are crucial for their anti-HBV potency.     

Adenosine derivatives with N6-alkyl, -alkylamine or -alkyladenosine substituents as probes for the A1-receptor

Three series of N6-substituted adenosine derivatives were synthesized, having in common an unbranched alkyl chain with lengths varying from 2 to 12 methylene units, but differing in their omega-alkyl substituents: N6-n-alkyladenosines (I), N6-omega-amino-alkyladenosines (II) and alpha omega,di-(adenosin-N6-yl)alkanes (III). The compounds of the latter series combine two functional groups in one molecule. A1-receptor affinity of these compounds was measured as inhibition of [3H]PIA binding to calf brain membranes. With relatively short chain lengths, compounds in series I are the most potent. In this series, optimum activity is reached with N6-n-pentyladenosine (Ki = 0.50 nM). With short chain lengths, compounds in series II and III are 6-20-fold less potent than their congeners in series I. The potency order however is reversed with higher chain lengths. While affinity in series II and III increases strongly, reaching an optimum with the nonyl derivatives, affinity in series I decreases sharply with alkyl chains larger than 8 methylene units. Highest affinity is found with 9-amino-nonyladenosine (Ki = 0.32 nM). In general, the omega-aminoalkyl derivatives are somewhat more potent than the corresponding di-adenosinyl derivatives. Implications for the possible topography of the N6 region of the A1-receptor and the area further removed from N6 are discussed.     

Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors with activity in animal models of schizophrenia

A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model.