GLEPP1/protein-tyrosine phosphatase phi inhibitors block chemotaxis in vitro and in vivo and improve murine ulcerative colitis.

We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase . Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1.

In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties.

Non-competitive N-methyl-d-aspartate (NMDA) blockers induce schizophrenic-like behavior in healthy volunteers and exacerbate symptomatology in schizophrenic patients. Hence, a compound able to enhance NMDA neurotransmission by increasing levels of d-serine, an endogenous full agonist at the glycine site of the NMDA receptors, could have anti-psychotic activity. One way to increase d-serine levels is the inhibition of d-amino acid oxidase (DAAO), the enzyme responsible for d-serine oxidation.

Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists.

We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes.

Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase.

Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored.

Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase.

Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure--activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme.

3,6-dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation.

There is compelling evidence that Bax channel activity stimulates cytochrome c release leading ultimately to cell death, which is a key event in ischemic injuries and neurodegenerative diseases. Here 3,6-dibromocarbazole piperazine derivatives of 2-propanol are described as the first small and potent modulators of the cytochrome c release triggered by Bid-induced Bax activation in a mitochondrial assay. Furthermore, a mechanism of action is proposed, and fluorescent derivatives allowing the localization of such inhibitors are reported.

F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine.

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.

Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses.

The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs.

Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors.

Hybrid molecules built up by covalent coupling of aminopropanol derivatives (especially pindolol) with antidepressant drugs like fluoxetine, paroxetine or milnacipran were found to be potent and silent 5-HT1A antagonists (KB < 1 nM for 7c and 9a).

Dimers of 5HT1 ligands preferentially bind to 5HT1B/1D receptor subtypes.

New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent.

Sulfonamide derivatives of benzylamine block cholesterol biosynthesis in HepG2 cells: a new type of potent squalene epoxidase inhibitors.

Sulfonamide derivatives of ene-yne benzylamine 1 have been prepared and identified as a new class of potent SE inhibitors having demonstrated activity in HepG2 cells as cholesterol biosynthesis inhibitors.

Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist.

A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.

Dimerization of 8-OH-DPAT increases activity at serotonin 5-HT1A receptors.

[35S]GTPgammaS binding responses can be used to measure differences between the intrinsic activity of ligands at human 5-hydroxytrypamine-(1A) (h 5-HT1A) receptors expressed in recombinant cell lines. The maximal [35S]GTPgammaS binding response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was lower than that to 5-HT in a recombinant C6-glial membrane preparation and dependent on the GDP concentration: it was attenuated by about 60% vs 5-HT by increasing the concentration of GDP from 0.3 to 30 and 300 microM.

5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine.

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives.

Differentiation between partial agonists and neutral 5-HT1B antagonists by chemical modulation of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (GR-55562).

The synthesis and binding affinity at cloned h5-HT1D, h5-HT1D, and h5-HT1A receptors of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (2, GR-55562) and four O-methylated analogs are described. The functional activity of these compounds was determined at the h5-HT1B receptor using a [35S]GTP gamma S binding assay. The four analogs have been prepared in order to evaluate the influence of the alkylamino side chain conformation on binding and intrinsic activity.

[Inhibitors of Ras farnesylation: tomorrow's anticancer agents?].

Increasing evidence implicates a critical role for aberrant Ras function in promoting the development of human tumours and has provided the impetus for identifying anti-Ras drugs for therapy. In order to be active the protooncogene ras must be associated with the plasma membrane. This feature depends crucially upon its farnesylation (addition of a 15 carbon moiety) by the enzyme farnesyl protein transferase.

Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists.

A series of serotonin dimers of formula 4 in which two serotonin moeities are linked together through their 5-hydroxyl residue has been prepared and evaluated as 5-HT(1B/1D) receptor agonists. Binding experiments at cloned human 5-HT(1B), 5-HT(1D), and 5-HT(1A) receptors show that all of these dimers are very potent ligands at 5-HT(1B/1D) receptors with increased binding selectivity vs the 5-HT(1A) receptor when compared to serotonin. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5-HT(1B) receptor (formerly the 5-HT(1Dbeta) receptor) demonstrate that all of these serotonin dimers behave as full agonists.

Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors.

A series of new arylpiperazide derivatives of serotonin has been prepared and evaluated as 5-HT1D receptor agonists. Binding experiments at cloned human 5-HT1D alpha, 5-HT1D beta, and 5-HT1A receptors show that all the compounds are very potent and selective ligands for 5-HT1D receptor subtypes. Functional activity studies (contraction of the New Zealand white rabbit saphenous vein) demonstrate that most of the derivatives behave as full agonists.

(Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors.

A series of 3-substituted (aryloxy)silane derivatives of benzylamine (4, 4', or 4") was synthesized and evaluated for hypocholesterolemic activity. Most of the new silane derivatives were identified as potent inhibitors of pig liver squalene epoxidase with IC50 values in the submicromolar range. In vitro inhibition of cholesterol biosynthesis in Hep-G2 cells was observed with a very good potency for the ene-yne derivatives 4a, 4i, 4n, 4q, and 4u as well as for the yne-yne compound 4".

Synthesis, antiviral activity and enzymatic phosphorylation of 9-phosphonopentenyl derivatives of guanine.

(E)-9-(5-Phosphonopent-4-enyl)guanine and (E)-9-[3-(hydroxymethyl)-5- phosphonopent-4-enyl]guanine which bear a vinyl phosphonate moiety as a mimic of the phosphate group were synthesized. Their activities against human immunodeficiency virus type-1 (HIV-1), herpes simplex virus type-1 (HSV-1) and human cytomegalovirus (HCMV) were evaluated in vitro in parallel with those of 9-(5-phosphonopentyl)guanine and 9-(5,5-difluoro-5- phosphonopentyl)guanine. Both vinyl phosphonates exhibited anti-HIV-1 and anti-HCMV activities, whereas the methyl- and difluoromethyl phosphonate analogues were inactive.

Enzymatic phosphorylation and pyrophosphorylation of 2',3'-dideoxyadenosine-5'-monophosphate, a key metabolite in the pathway for activation of the anti-HIV (human immunodeficiency virus) agent 2',3'-dideoxyinosine.

2',3'-Dideoxyadenosine-5'-monophosphate (ddAMP) is a key intermediate in the metabolic pathway involved in the activation of the anti-retroviral agent 2',3'-dideoxyinosine (ddI) to 2',3'-dideoxyadenosine-5'-triphosphate (ddATP). The potential phosphorylation of ddAMP by adenylate kinase (myokinase) and pyrophosphorylation by the reverse reaction of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase were investigated. Using ATP as phosphate donor, ddAMP was phosphorylated by adenylate kinase with an efficiency of 8.

9-(Phosphonoalkyl)guanine derivatives as substrates or inhibitors of guanylate kinase.

Several 9-(phosphonoalkyl)guanines (Gua(CH2)nCH2-PO3H2; n = 4-6) and 9-(difluorophosphonoalkyl)guanines (Gua(CH2)nCF2PO3H2; n = 3-7) were studied as potential substrates and inhibitors of guanylate kinase. These compounds are inhibitors of the enzyme except 9-(5-phosphonopentyl)guanine (n = 4) which is a substrate with an efficiency of phosphorylation of about 0.3% that of GMP, as estimated from the Vmax/Km ratios.