from C-N single bonds may slightly influence the momenta as well. We expect polymers with structu... more from C-N single bonds may slightly influence the momenta as well. We expect polymers with structures like 1 to be highly dipolar rigid rods, by virtue of the significant dipole moment contributed by each segment and the nearly perfect projection of the moments along the rigid rod axis assured by the imino connector. More extended *-electron systems, such as stilbenediyl or azodiphenyl, could in principle be substituted for the phenylene units in 1, possibly giving rise to enhanced dipolar or optical effects. Efforta to synthesize these polymers and apply them as described in the introduction are currently in progress. Supplementary Material Available: Preparation and characterization of 2-6 (3 pages). Ordering information is given on any current masthead page.
Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compoun... more Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compounds bearing an ortho-substituted propionic acid moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinities of key compound on all eight human prostanoid receptors is reported.
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inh... more Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2012
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperid... more The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Bioorganic & Medicinal Chemistry Letters, May 1, 2006
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs b... more Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Bioorganic & Medicinal Chemistry Letters, Feb 1, 2008
The structure–activity relationship of a novel series of 8-biarylquinolines acting as type 4 phos... more The structure–activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC50<10nM) isozymes (A–D). In a human whole blood in vitro assay, they inhibit (IC50<0.5μM) the LPS-induced release of the cytokine TNF-α. Optimized inhibitors were evaluated in
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a numbe... more Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.
Bioorganic & Medicinal Chemistry Letters, Dec 1, 2005
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein d... more The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood…
A novel photoaffinity probe for the leukotriene D4 receptor (LTD4) is described. L-745310, which ... more A novel photoaffinity probe for the leukotriene D4 receptor (LTD4) is described. L-745310, which is structurally related to the potent LTD4 antagonist MK-0476 (Singulair), was found to selectively label a 43-kDa protein in guinea-pig lung membrane previously identified as the LTD4 receptor.
Bioorganic & Medicinal Chemistry Letters, Feb 1, 2005
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activ... more A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E 2 receptors evaluated. Many of them are very potent and selective EP 3 antagonists (K i 3-10 nM), while compound 9 is a very good and selective EP 2 agonist (K i 8 nM). The biological profile of the EP 2 agonist 9 in vivo and the metabolic profile of selected EP 3 antagonists are also reported.
Bioorganic & Medicinal Chemistry Letters, Nov 1, 2010
The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type ... more The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
La presente invention concerne des derives d'indole ayant la formule (I) et qui ont une activ... more La presente invention concerne des derives d'indole ayant la formule (I) et qui ont une activite sur les recepteurs cannabinoides. L'invention concerne aussi les procedes de preparation de ces derives. Ces composes sont utiles pour abaisser la pression oculaire intra-oculaire et pour traiter le glaucome en raison de l'activite du recepteur cannabinoide.
Medicinal chemistry Medicinal chemistry V 1100 Structure-Activity Relationship of Biaryl Acylsulf... more Medicinal chemistry Medicinal chemistry V 1100 Structure-Activity Relationship of Biaryl Acylsulfonamide Analogues on the Human EP 3 Prostanoid Receptor.-The preparation of a combinatorial library of 750 compounds leads to the identification of potent and selective EP 3 and EP 1 ligands. Introduction of an acidic moiety, consisting of a two carbon tethered acyl sulfonamide, into the ortho-position of the biaryl scaffold improves the affinity for the EP 3 receptor. Finally, structure-activity relationship examinations of the lipophilic residue result in the potent EP 3 antagonists (I). Dichlorophenyl analogue (Ib) is identified as a potent and selective ligand with an acceptable selectivity profile against all eight prostanoid receptors.-(GALLANT*,
from C-N single bonds may slightly influence the momenta as well. We expect polymers with structu... more from C-N single bonds may slightly influence the momenta as well. We expect polymers with structures like 1 to be highly dipolar rigid rods, by virtue of the significant dipole moment contributed by each segment and the nearly perfect projection of the moments along the rigid rod axis assured by the imino connector. More extended *-electron systems, such as stilbenediyl or azodiphenyl, could in principle be substituted for the phenylene units in 1, possibly giving rise to enhanced dipolar or optical effects. Efforta to synthesize these polymers and apply them as described in the introduction are currently in progress. Supplementary Material Available: Preparation and characterization of 2-6 (3 pages). Ordering information is given on any current masthead page.
Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compoun... more Potent and selective ligands for the human EP3 prostanoid receptor are described. Triaryl compounds bearing an ortho-substituted propionic acid moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinities of key compound on all eight human prostanoid receptors is reported.
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inh... more Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Bioorganic & Medicinal Chemistry Letters, Mar 1, 2012
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperid... more The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Bioorganic & Medicinal Chemistry Letters, May 1, 2006
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs b... more Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Bioorganic & Medicinal Chemistry Letters, Feb 1, 2008
The structure–activity relationship of a novel series of 8-biarylquinolines acting as type 4 phos... more The structure–activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC50<10nM) isozymes (A–D). In a human whole blood in vitro assay, they inhibit (IC50<0.5μM) the LPS-induced release of the cytokine TNF-α. Optimized inhibitors were evaluated in
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a numbe... more Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.
Bioorganic & Medicinal Chemistry Letters, Dec 1, 2005
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein d... more The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood…
A novel photoaffinity probe for the leukotriene D4 receptor (LTD4) is described. L-745310, which ... more A novel photoaffinity probe for the leukotriene D4 receptor (LTD4) is described. L-745310, which is structurally related to the potent LTD4 antagonist MK-0476 (Singulair), was found to selectively label a 43-kDa protein in guinea-pig lung membrane previously identified as the LTD4 receptor.
Bioorganic & Medicinal Chemistry Letters, Feb 1, 2005
A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activ... more A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E 2 receptors evaluated. Many of them are very potent and selective EP 3 antagonists (K i 3-10 nM), while compound 9 is a very good and selective EP 2 agonist (K i 8 nM). The biological profile of the EP 2 agonist 9 in vivo and the metabolic profile of selected EP 3 antagonists are also reported.
Bioorganic & Medicinal Chemistry Letters, Nov 1, 2010
The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type ... more The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
La presente invention concerne des derives d'indole ayant la formule (I) et qui ont une activ... more La presente invention concerne des derives d'indole ayant la formule (I) et qui ont une activite sur les recepteurs cannabinoides. L'invention concerne aussi les procedes de preparation de ces derives. Ces composes sont utiles pour abaisser la pression oculaire intra-oculaire et pour traiter le glaucome en raison de l'activite du recepteur cannabinoide.
Medicinal chemistry Medicinal chemistry V 1100 Structure-Activity Relationship of Biaryl Acylsulf... more Medicinal chemistry Medicinal chemistry V 1100 Structure-Activity Relationship of Biaryl Acylsulfonamide Analogues on the Human EP 3 Prostanoid Receptor.-The preparation of a combinatorial library of 750 compounds leads to the identification of potent and selective EP 3 and EP 1 ligands. Introduction of an acidic moiety, consisting of a two carbon tethered acyl sulfonamide, into the ortho-position of the biaryl scaffold improves the affinity for the EP 3 receptor. Finally, structure-activity relationship examinations of the lipophilic residue result in the potent EP 3 antagonists (I). Dichlorophenyl analogue (Ib) is identified as a potent and selective ligand with an acceptable selectivity profile against all eight prostanoid receptors.-(GALLANT*,
Uploads
Papers by Michel Gallant