The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB1 receptor inverse agonists (CB1RIAs) that have been reported to attenuate obesity and improve insulin sensitivity in the diet-induced obese (DIO) mouse model. However, chronic dosing of select compounds from the series showed time-dependent brain accumulation despite a low brain/plasma exposure ratio. To address this issue, a PEGylation approach was employed to identify a novel series of homodimeric 6-benzhydryl-4-amino-quinazoline-PEG conjugates with an extended half-life. The lead compound 18 engaged peripheral CB1Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study.
Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50â¯=â¯45â¯nM), and excellent potency at SGLT2 (IC50â¯=â¯1â¯nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (Fâ¯=â¯78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24â¯h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.
Benzene Derivatives/pharmacology , Cyclobutanes/pharmacology , Glycosides/pharmacology , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 2 Inhibitors , Administration, Oral , Animals , Benzene Derivatives/administration & dosage , Benzene Derivatives/chemistry , Cyclobutanes/administration & dosage , Cyclobutanes/chemistry , Dogs , Dose-Response Relationship, Drug , Glycosides/administration & dosage , Glycosides/chemistry , Haplorhini , Humans , Mice , Molecular Structure , Rats , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 2/metabolism , Structure-Activity Relationship
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hypoglycemic Agents/pharmacology , Pyrroles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Dose-Response Relationship, Drug , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Mice , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship
We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Design , HEK293 Cells , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/therapeutic use , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Mice, Inbred C57BL , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship
We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).
A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.
Diabetes Mellitus/drug therapy , Gallbladder Emptying/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Imidazoles/chemistry , Imidazoles/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Cell Line , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Diabetes Mellitus/physiopathology , Humans , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacology , Methylation , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolism
Phosphonium salt-activated, Pd-catalyzed Suzuki-Miyaura and Sonogashira cross-coupling reactions of cyclic 1,3-diones in the synthesis of ß-substituted cyclic enones are described. These transformations exhibit good isolated yield and high generality with respect to both substrates and coupling partners. Extension of the substrate scope to cyclic 1,3-dione equivalents, such as 2-cyanocyclohexanone (4), is also briefly examined.
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Quinolones/pharmacology , Topoisomerase Inhibitors/pharmacology , Humans
Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
Bridged Bicyclo Compounds/chemistry , Enzyme Inhibitors/chemistry , Pyridazines/chemistry , Stearoyl-CoA Desaturase/antagonists & inhibitors , Administration, Oral , Animals , Body Weight/drug effects , Drug Design , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Obesity/drug therapy , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Pyridazines/therapeutic use , Rats , Rats, Sprague-Dawley , Rats, Zucker , Stearoyl-CoA Desaturase/metabolism , Structure-Activity Relationship
A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Urea/analogs & derivatives , Administration, Oral , Animals , Body Weight/drug effects , Diet , Enzyme Activation/drug effects , Enzyme Inhibitors/therapeutic use , Mice , Mice, Inbred C57BL , Obesity/drug therapy , Piperidines/metabolism , Protein Binding , Rats , Stearoyl-CoA Desaturase/metabolism , Structure-Activity Relationship , Urea/metabolism , Urea/pharmacology
The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6nM with 34 being the most potent compound discovered (MMP-2 IC(50)=0.39nM and MMP-9 IC(50)=0.22nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.
Azepines/pharmacology , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/pharmacology , Azepines/pharmacokinetics , Biological Availability , Cyclization , Drug Discovery , Inhibitory Concentration 50 , Protease Inhibitors/pharmacokinetics , Stereoisomerism
The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.
Alkynes/chemistry , Heterocyclic Compounds/chemistry , Organophosphorus Compounds/chemistry , Catalysis , Copper/chemistry , Palladium/chemistry
2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50=26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F=53%) and long human liver microsome stability (t(1/2)=62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.
Benzoxazines/chemical synthesis , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Drug Design , Administration, Oral , Animals , Benzoxazines/chemistry , Benzoxazines/pharmacology , Cholesterol Ester Transfer Proteins/genetics , Cricetinae , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Transgenic , Molecular Structure , Rats
The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent JAK3 activity against isolated enzyme and in T-cells. One analog (32) showed unique biological effects during in vitro and in vivo tests including inhibition of STAT5 phosphorylation, blockade of mast cell responses, and reduction of JAK3 based effects in mice models of allergic disease.
Hypersensitivity/drug therapy , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Staurosporine/chemical synthesis , Animals , Cyclization , Drug Evaluation, Preclinical , Mast Cells/drug effects , Mice , Phosphorylation/drug effects , STAT5 Transcription Factor/metabolism , Structure-Activity Relationship , T-Lymphocytes/enzymology
2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
Antineoplastic Agents/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/analogs & derivatives , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor/methods , Humans , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Administration, Oral , Animals , Cricetinae , Dietary Fats/administration & dosage , Drug Design , Humans , Macaca fascicularis , Magnetic Resonance Spectroscopy , Mice , Quinolines/chemical synthesis , Spectrometry, Mass, Electrospray Ionization
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
Glycolates/chemical synthesis , Glycolates/pharmacology , PPAR delta/agonists , Combinatorial Chemistry Techniques , Drug Design , Drug Discovery , Drug Evaluation, Preclinical , Glycolates/chemistry , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiazoles/pharmacology
The first direct arylation via C-OH bond activation of tautomerizable heterocycles has been achieved using phosphonium salts, on the basis of a combination of the phosphonium coupling and Suzuki-Miyaura cross-coupling conditions. Optimal reaction condition is obtained through screening of phosphonium salts, Pd catalysts, and bases. The direct arylation via C-OH bond activation tolerates a variety of tautomerizable heterocycles and aryl boronic acids. The mechanism of the Pd-catalyzed phosphonium coupling is proposed to proceed via a domino seven-step process including the unprecedented heterocycle-Pd(II)-phosphonium species. Application of the Pd-catalyzed direct arylation via C-OH bond activation using PyBroP leads to the most efficient synthesis of the biologically important 6-arylpurine ribonucleoside in a single step from unactivated and unprotected inosine.
Boronic Acids/chemistry , Carbon/chemistry , Heterocyclic Compounds/chemistry , Hydroxides/chemistry , Organophosphonates/chemistry , Palladium/chemistry , Catalysis , Models, Chemical