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1.
J Med Chem ; 57(8): 3430-49, 2014 Apr 24.
Article in English | MEDLINE | ID: mdl-24641103

ABSTRACT

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.


Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Naphthyridines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Dogs , Drug Discovery , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Macaca fascicularis , Naphthyridines/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Structure-Activity Relationship , U937 Cells , fms-Like Tyrosine Kinase 3/genetics
2.
Pharmacol Res Perspect ; 1(1): e00003, 2013 Oct.
Article in English | MEDLINE | ID: mdl-25505557

ABSTRACT

Melanin-concentrating hormone (MCH) regulates food intake through activation of the receptor, MCHR1. We have identified AMG 076 as an orally bioavailable potent and selective small molecule antagonist of MCHR1. In mouse models of obesity, AMG 076 caused a reduction in body weight gain in wild-type (MCHR1+/+) but not in knockout (MCHR1-/-) mice. The body weight reduction was associated with decreases in food intake and increases in energy expenditure. Importantly, we show that these MCHR1-dependent effects of AMG 076 were also reflected in improved metabolic phenotypes, increased glucose tolerance and insulin sensitivity. Preliminary data on effects of AMG 076 in obese cynomolgus monkeys are also presented.

3.
Bioorg Med Chem Lett ; 22(11): 3781-5, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22542010

ABSTRACT

An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.


Subject(s)
Carbazoles/chemistry , Cyclohexanecarboxylic Acids/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacokinetics , Diet, High-Fat , Dogs , Drug Evaluation, Preclinical , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Rats , Receptors, Pituitary Hormone/genetics , Receptors, Pituitary Hormone/metabolism , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 22(5): 2046-51, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22305493

ABSTRACT

A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.


Subject(s)
Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolism , Animals , Benzodiazepines/metabolism , Benzodiazepines/pharmacokinetics , Calcium/metabolism , Cell Line , Hepatocytes/metabolism , Humans , Luminescent Measurements , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 21(23): 7001-5, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-22019296

ABSTRACT

A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model.


Subject(s)
Anti-Obesity Agents/chemistry , Drug Discovery , Indoles/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Dogs , Eating/drug effects , HEK293 Cells , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Inhibitory Concentration 50 , Macaca mulatta , Molecular Structure , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 18(2): 608-13, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18063364

ABSTRACT

A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.


Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Drug Design , Humans , Imidazoles/pharmacokinetics , Mice , Mice, Knockout , Rats , Receptors, CXCR3/genetics , Receptors, CXCR3/physiology , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 18(2): 688-93, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18061451

ABSTRACT

A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.


Subject(s)
Heterocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Animals , Chromatography, High Pressure Liquid , Humans , Quinazolinones/pharmacokinetics , Rats , Stereoisomerism
8.
J Org Chem ; 67(20): 6871-7, 2002 Oct 04.
Article in English | MEDLINE | ID: mdl-12353976

ABSTRACT

Several analogues of a hypothetical intermediate in the reaction catalyzed by lumazine synthase were synthesized and tested as inhibitors of both Bacillus subtilis lumazine synthase and Escherichia coli riboflavin synthase. The new compounds were designed by replacement of a two-carbon fragment of several 5-phosphonoalkyl-6-D-ribitylaminopyrimidinedione lumazine synthase inhibitors with an amide linkage that was envisioned as an analogue of a Schiff base moiety of a hypothetical intermediate in the enzyme-catalyzed reaction. The incorporation of the amide group led to an unexpected reversal in selectivity for inhibition of lumazine synthase vs riboflavin synthase. Whereas the parent 5-phosphonoalkyl-6-D-ribitylaminopyrimidinediones were lumazine synthase inhibitors and did not inhibit riboflavin synthase, the amide-containing derivatives inhibited riboflavin synthase and were only very weak or inactive as lumazine synthase inhibitors. Molecular modeling of inhibitor-lumazine synthase complexes did not reveal a structural basis for these unexpected findings. However, molecular modeling of one of the inhibitors with E. coli riboflavin synthase demonstrated that the active site of the enzyme could readily accommodate two ligand molecules.


Subject(s)
Amides/chemistry , Enzyme Inhibitors/chemical synthesis , Multienzyme Complexes/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Riboflavin Synthase/antagonists & inhibitors , Binding Sites , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Kinetics , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Multienzyme Complexes/chemistry , Protein Conformation , Pteridines , Riboflavin Synthase/chemistry , Structure-Activity Relationship
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