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At least 307 records · Page 17Linked to original sources
PubMed2005

6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 adenosine receptor agonist allosteric enhancers having improved potency.

Allosteric enhancers (AEs) of the A(1) adenosine receptor (A(1)AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A(1)AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a-aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a-aj. Binding studies using membranes from cells stably expressing human A(1)ARs, A(2A)ARs, or A(3)ARs evaluated AE activity and receptor subtype selectivity. The EC(50) of the AE activities of compounds 3m-o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 muM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 microM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A(2A)AR and only minimal activity at the A(3)AR.

Adenosine A1 Receptor Agonists↗
PubMed2004

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.

Adenosine Triphosphate↗
PubMed2004

Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel.

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.

Administration, Oral↗
PubMed2006

Discovery and evaluation of N-cyclopropyl- 2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5- ylmethyl)amino)benzamide (BMS-605541), a selective and orally efficacious inhibitor of vascular endothelial growth factor receptor-2.

Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.

Administration, Oral↗
PubMed2006

[4-(imidazol-1-yl)thiazol-2-yl]phenylamines. A novel class of highly potent colchicine site binding tubulin inhibitors: synthesis and cytotoxic activity on selected human cancer cell lines.

Synthesis and cytotoxic activity in the submicromolar range of a series of [4-(imidazol-1-yl)thiazol-2-yl]phenylamines are described. Cell cycle dependent cytotoxicity on RKO human colon carcinoma cells with inducible expression of p27(kip1) and the influence on microtubule formation were investigated. Considering the significant correlation between the IC(50) values of tubulin polymerization inhibition, [(3)H]colchicine competition, and cytotoxicity of the investigated compounds, tubulin is the main cellular target. The inhibition of microtubule formation was shown to be mediated by interference with the colchicine binding site of tubulin. In depth analysis of the investigated compounds allowed the identification of modifications that altered the pharmacological profile of the compounds from a mitosis-inducing phenotype to a G1 cell cycle arresting phenotype.

Aniline Compounds↗
PubMed1996

Potential antitumor agents. 24. Synthesis and pharmacological behavior of imidazo[2,1-b]thiazole guanylhydrazones bearing at least one chlorine.

In connection with a previous research dealing with the antitumor activity of imidazo[2,1-b]-thiazole guanylhydrazones, this paper reports the synthesis of new derivatives which were tested for antitumor and positive inotropic activity. In most cases the cytotoxic data from the in vitro experiments (HeLa) were in agreement with the antitumor data in vivo (Ehrlich). The active compounds bear a phenyl ring at the 6 position. On the other hand, the most active cardiotonic agents were devoid of the phenyl ring.

Animals↗
PubMed1997

New orally active non-peptide fibrinogen receptor (GpIIb-IIIa) antagonists: identification of ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl) imino]methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl]pip erid -4-yl]amino]propionate (SR 121787) as a potent and long-acting antithrombotic agent.

The platelet fibrinogen receptor GpIIb-IIIa is currently considered a target of choice for drugs used in the prevention and treatment of thrombosis. Ethyl 3-[N-[4-[4-[amino[(ethoxycarbonyl)-imino] methyl]phenyl]-1,3-thiazol-2-yl]-N-[1-[(ethoxycarbonyl)methyl] piperid-4-yl] amino]propionate (6, SR 121787) is a new antiaggregating agent which generates in vivo the corresponding diacid 19d (SR 121566), non-peptide GpIIb-IIIa antagonist. In vitro, 19d inhibited ADP-induced aggregation of human and baboon platelets (IC50 = 46 +/- 11 and 54 +/- 6 nM, respectively), and on human platelets, 19d antagonized the binding of 125I-labeled fibrinogen (IC50 = 19.2 +/- 6.2 nM). Ex vivo, 8 h after an i.v. administration of 19d (100 micrograms/kg, i.v.) to baboons, ADP-induced aggregation was strongly inhibited (more than 90%). At 8 h, the ED50 value was 24 +/- 3.3 micrograms/kg), and even 24 h after the administration of a single dose of 100 micrograms/kg of 19d, platelet aggregation was still significantly inhibited (50 +/- 6% inhibition, P < 0.05). In the same species, the oral administration of 500 micrograms/kg of 6 produced a nearly complete inhibition of aggregation for up to 8 h (ED50 at 8 h was 193 +/- 20 micrograms/kg). After an oral dose of 2 mg/kg of 6, an antiaggregating effect was still observed at 24 h (44 +/- 12% inhibition, P < 0.05). 6 was well tolerated in animals, showing that, on the basis of these studies, it is a suitable candidate for development as an orally active antithrombotic agent.

Adenosine Diphosphate↗
PubMed1998

Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents.

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Animals↗
PubMed2003

Total synthesis of dendroamide a: oxazole and thiazole construction using an oxodiphosphonium salt.

The total synthesis of dendroamide A (1), a multidrug-resistance reversing bistratamide-type peptide-derived macrocycle, has been accomplished in 19% yield. Fmoc-protected amino acids were condensed into appropriately protected dipeptides which were treated with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate to afford oxazoles and thiazolines (oxidized to thiazoles) with high chemo- and stereoselectivity. The convergent condensation of three heterocyclic amino acids followed by macrocyclization afforded the natural product.

Amino Acids↗
PubMed2006

Access to piperidine imino-C-glycosides via stereoselective thiazole-based aminohomologation of pyranoses.

The access to piperidine homoazasugars (dideoxyiminoheptitols) from pyranoses via formal one-carbon chain elongation and exchange of the ring oxygen with the NH group is described. The key process involves the stereoselective addition of 2-thiazolylmagnesium bromide to an N-glycosylhydroxylamine, i.e., a hidden open-chain sugar nitrone. The N-thiazolylalkylhydroxylamine formed in this way is reduced to amine, and this transformed into a substituted piperidine via intramolecular cyclization by an S(N)2 process. Cleavage of the thiazole residue attached to C2 of the piperidine ring reveals the formyl group, and this is reduced to hydroxymethyl to give the target homoazasugar. A collection of six stereodiversified compounds with free OH and NH groups and isolated as hydrochlorides has been prepared.

Amines↗
PubMed2000

Titanium(IV)-mediated tandem deprotection-cyclodehydration of protected cysteine N-amides: biomimetic syntheses of thiazoline- and thiazole-containing heterocycles.

The scope and limitations of TiCl(4)-mediated Delta(2)-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the stereochemical outcomes vary on the basis of structural considerations and reaction conditions (22-99% ee). Racemization at the C(2)-exomethine position limits the utility of this method for the formation of a thiazoline within a peptide. Treatment of a tritylated Cys-Cys dipeptide with TiCl(4) afforded the corresponding thiazole-thiazoline heterocycle 12 (38% yield, 97% ee).

Amides↗
PubMed2002

Regiocontrolled synthesis of substituted thiazoles.

The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described. [reaction: see text]

Catalysis↗
PubMed2002

Regioselective synthesis of antiparallel loops on a macrocyclic scaffold constrained by oxazoles and thiazoles.

The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking multiple loops of proteins.[structure: see text]

Magnetic Resonance Spectroscopy↗
PubMed2004

Thiazole orange-peptide conjugates: sensitivity of DNA binding to chemical structure.

[structure: see text] Derivatives of the highly fluorescent and DNA-binding dye thiazole orange (TO) are described that feature appended peptides. Functionalization of TO can be achieved at either of the endocyclic nitrogens, and the photophysical properties and DNA-binding modes are sensitive to the position of the tethered peptide. A series of TO-peptide conjugates are described, demonstrating the utility of a solid-phase synthesis approach to their preparation and illustrating how the photophysical and DNA-binding properties of the compounds are influenced by chemical structure.

Amino Acid Sequence↗
PubMed2006

Self-condensation of a thiazole-peptide bearing a 21-membered loop into a library of giant macrocycles with multiple orthogonal loops.

[reaction: see text] Tetrapeptide analogue H-[Glu-Ser-Lys(Thz)]-OH, containing a turn-inducing thiazole constraint, was used as a template to produce a 21-membered structurally characterized loop by linking Glu and Lys side chains with a Val-Ile dipeptide. This template was oligomerized in one pot to a library (cyclo-[1](n)(), n = 2-10) of giant symmetrical macrocycles (up to 120-membered rings), fused to 2-10 appended loops that were carried intact through multiple oligomerization (chain extension) and cyclization (chain terminating) reactions of the template. A three-dimensional solution structure for cyclo-[1](3) shows all three appended loops projecting from the same face of the macrocycle. This is a promising approach to separating peptide motifs over large distances.

Cyclization↗
PubMed2006

C-15 thiazol-4-yl analogues of (E)-9,10-didehydroepothilone D: synthesis and cytotoxicity.

The syntheses and biological evaluation of six epothilone D analogues are reported. These side-chain variants of the (E)-9,10-didehydroepothilone scaffold contain C-15 thiazole appendages that are derived from bromomethyl ketone intermediates. Although each of these analogues is less cytotoxic than the parent (E)-9,10-didehydroepothilone D, three maintain IC(50) values in the double-digit nanomolar range against both susceptible and resistant cell lines.

Antineoplastic Agents↗
PubMed1999

Ab initio calculations on peptide-derived oxazoles and thiazoles: improved molecular mechanics parameters for the AMBER force field.

Ab initio calculations at the RHF/6-31G* and MP2/6-31G*//RHF/6-31G* levels of theory are performed for 2-methyl-4-carboxamido-oxazoles and -thiazoles, including rotational profiles for the ring-carboxamide bond, which showed the expected conjugation and hydrogen bonding effects. On the basis of these data, newly optimised stretch, bend and torsional parameters for the AMBER* force field are derived, along with CHELPG-fitted partial atomic charges.

Models, Molecular↗