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2.
Bioorg Med Chem ; 24(10): 2215-34, 2016 05 15.
Article in English | MEDLINE | ID: mdl-27085672

ABSTRACT

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Amination , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Point Mutation , Protein Conformation, alpha-Helical/drug effects , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Structure-Activity Relationship
3.
J Med Chem ; 57(23): 9796-810, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25389560

ABSTRACT

The optimization of a series of aminooxazoline xanthene inhibitors of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aß lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aß reduction in a rat pharmacodynamic model (78% Aß reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Oxazolone/analogs & derivatives , Protease Inhibitors/chemical synthesis , Xanthenes/chemical synthesis , Animals , Crystallography, X-Ray , HEK293 Cells , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Oxazolone/chemical synthesis , Oxazolone/pharmacology , Rats, Sprague-Dawley , Structure-Activity Relationship , Xanthenes/pharmacology
4.
J Med Chem ; 56(24): 10003-15, 2013 Dec 27.
Article in English | MEDLINE | ID: mdl-24294969

ABSTRACT

Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting ß-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.


Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Tankyrases/antagonists & inhibitors , Administration, Oral , Biological Availability , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tankyrases/metabolism
5.
Bioorg Med Chem Lett ; 22(17): 5392-5, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22877629

ABSTRACT

Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.


Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Casein Kinase I/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Benzimidazoles/pharmacokinetics , Binding Sites , Casein Kinase I/chemistry , Casein Kinase I/metabolism , Humans , Mice , Models, Molecular , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , beta Catenin/metabolism
6.
ACS Med Chem Lett ; 3(12): 1059-64, 2012 Dec 13.
Article in English | MEDLINE | ID: mdl-24900428

ABSTRACT

Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms. A single oral dose of compound 13 resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.

7.
Tetrahedron Lett ; 49(45): 6383-6385, 2008 Nov 03.
Article in English | MEDLINE | ID: mdl-19890380

ABSTRACT

The paper describes a short and biomimetic synthesis of tricycloillicinone, which was found to enhance the action of choline acetyltransferase (ChAT). The synthetic route has two critical reactions: bulky, oxygenophilic methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) promoted rearrangement of prenyl phenyl ether and photochemical cyclization. Furthermore, experiments were designed to explore the process of MABR promoted rearrangement. It was found that stereochemistry of deuterium labeled prenyl group was only partially scrambled, which suggests that there may be two possible reaction pathways involved in this process. It also suggests that the direct migration of prenyl group to para-position under these conditions is slightly favored over the Claisen-Cope process. The highly efficient synthetic route also provides important new opportunities to explore the biological behavior of tricycloillicinone.

10.
J Am Chem Soc ; 128(3): 1016-22, 2006 Jan 25.
Article in English | MEDLINE | ID: mdl-16417394

ABSTRACT

The total synthesis of jiadifenin has been accomplished. The synthesis allows us to build an SAR profile which suggests that the jiadifenin skeleton may be less desirable from the standpoint of nominating a potential drug than that of its prerearrangement precursor. The key steps of the jiadifenin problem involve the construction of two 1,3-related quaternary carbons. The paper describes how the stereochemistry was managed in this context. The issue was studied in considerable detail at the level of a then new allyl transfer reaction arising from a palladium-mediated transfer process of an allyl carbonate. By use of externally deuterated diallyl carbonate, we could probe, for the first time, the stereochemical relationship between the inter- and intramolecular versions of this process. The existence of concurrent inter- and intramolecular allylation reactions was demonstrated by deuteration experiments. While in the particular case at hand, we find very little difference in stereochemical outcome as one partitions between the inter- and intramolecular pathways, the techniques employed are applicable to other systems.


Subject(s)
Allyl Compounds/chemistry , Sesquiterpenes/chemical synthesis , Palladium/chemistry , Sesquiterpenes/pharmacology , Stereoisomerism , Structure-Activity Relationship
11.
Tetrahedron Lett ; 47(46): 8013-8016, 2006 Nov 13.
Article in English | MEDLINE | ID: mdl-17426819

ABSTRACT

A synthesis of EPO 114-166 glycopeptide (1), presenting the O-linked glycophorin of erythropoietin, is described.

12.
J Org Chem ; 70(24): 9849-56, 2005 Nov 25.
Article in English | MEDLINE | ID: mdl-16292815

ABSTRACT

[structure, reaction: see text] A full account of the total synthesis of neurotrophic compound NGA0187 is provided. A key feature of the synthesis involved the direct selective oxidation of 6alpha,7beta-diol to install the unusual 6,7-ketol moiety and stereoselective conjugate addition of vinyl cuprate to enone. A preliminary evaluation of its ability to stimulate the neurite outgrowth was also evaluated with PC12 cell.


Subject(s)
Neurons/drug effects , Triterpenes/chemical synthesis , Triterpenes/pharmacology , Animals , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Models, Molecular , Molecular Conformation , Nerve Growth Factor/pharmacology , PC12 Cells , Rats , Stereoisomerism , Structure-Activity Relationship , Triterpenes/chemistry
13.
Org Lett ; 6(16): 2689-91, 2004 Aug 05.
Article in English | MEDLINE | ID: mdl-15281745

ABSTRACT

Copper-catalyzed asymmetric conjugate addition of diethylzinc to nitroalkenes using new chiral monodentate phosphoramidite ligands proceeds with high enantioselectivity up to 99% ee. [reaction: see text]


Subject(s)
Alkenes/chemistry , Copper/chemistry , Nitro Compounds/chemistry , Organometallic Compounds/chemistry , Organophosphorus Compounds/chemistry , Catalysis , Ligands , Stereoisomerism
14.
Proc Natl Acad Sci U S A ; 101(15): 5411-6, 2004 Apr 13.
Article in English | MEDLINE | ID: mdl-15020764

ABSTRACT

Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6'-dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare and flexible for modifications. The fine-tuning capability of these ligands plays a significant role in achieving high enantioselectivity in the asymmetric hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to cycloalkenones.


Subject(s)
Organophosphorus Compounds/chemistry , Phenols/chemistry , Allyl Compounds/chemistry , Catalysis , Copper/chemistry , Cyanides/chemistry , Cyclohexanones/chemistry , Formates/chemistry , Ligands , Models, Molecular , Organometallic Compounds/chemistry , Organophosphorus Compounds/chemical synthesis , Phosphites/chemistry , Rhodium/chemistry , Stereoisomerism , Zinc/chemistry
15.
Org Lett ; 5(21): 3831-4, 2003 Oct 16.
Article in English | MEDLINE | ID: mdl-14535721

ABSTRACT

[reaction: see text] New monodentate phosphite ligands have been developed from axially chiral biphenols, which show excellent enantioselectivity in the Rh(I)-catalyzed hydrogenation of dimethyl itaconate. The new chiral ligand system is suitable to create libraries and possesses fine-tuning capability.


Subject(s)
Phosphites/chemical synthesis , Catalysis , Hydrogenation , Ligands , Models, Chemical , Molecular Structure , Phosphites/chemistry , Rhodium/chemistry , Stereoisomerism
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