ABSTRACT
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Subject(s)
Hypoglycemic Agents/chemical synthesis , PPAR alpha/agonists , PPAR gamma/agonists , Pyrrolidines/chemistry , Animals , Blood Glucose/analysis , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Female , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Ligands , Mice , Mice, Obese , PPAR alpha/metabolism , PPAR gamma/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/therapeutic use , Stereoisomerism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Subject(s)
Carboxylic Acids/chemistry , Drug Discovery , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Benzamidines , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Humans , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
Subject(s)
Breast Neoplasms , Cell Cycle , Cyclin-Dependent Kinases , Drug Discovery , Protein Kinase Inhibitors , Animals , Female , Humans , Mice , Apoptosis , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation , Cyclin-Dependent Kinase-Activating Kinase , Cyclin-Dependent Kinases/antagonists & inhibitors , Mice, Inbred BALB C , Mice, Nude , Protein Kinase Inhibitors/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Animals , Catalytic Domain , Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Humans , Insulin/blood , Insulin/metabolism , Mice , Mice, Inbred C57BL , Models, Molecular , Pyridines/pharmacokinetics , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , StereoisomerismABSTRACT
Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrimidines/chemistry , Dipeptidyl Peptidase 4/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
Subject(s)
Azoles/chemical synthesis , Drug Design , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Azoles/pharmacology , Cell Line/enzymology , Crystallography, X-Ray , Female , Humans , Hydrogen-Ion Concentration , Mice , Mice, Transgenic , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity RelationshipABSTRACT
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Kidney/metabolism , Sodium-Glucose Transporter 2 Inhibitors , Administration, Oral , Animals , Benzhydryl Compounds , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Glucosides/chemistry , Glucosides/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Rats , Sodium-Glucose Transporter 2 , StereoisomerismABSTRACT
3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
Subject(s)
Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Chemical and Drug Induced Liver Injury/etiology , Cholesterol/biosynthesis , Cholesterol/blood , Crystallography, X-Ray , Dogs , Female , Guinea Pigs , Haplorhini , Humans , Hydroxymethylglutaryl CoA Reductases/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/toxicity , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Models, Molecular , Muscle Cells/cytology , Muscle Cells/drug effects , Muscle Cells/metabolism , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/toxicityABSTRACT
Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.
Subject(s)
Carboxylic Acids , PPAR alpha/agonists , PPAR gamma/agonists , Piperidines , Binding, Competitive/drug effects , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
Subject(s)
Azetidines/chemistry , Azetidines/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Administration, Oral , Animals , Azetidines/chemical synthesis , Biological Availability , Copper/pharmacology , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Diabetes Mellitus, Experimental/drug therapy , Dyslipidemias/drug therapy , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Glucose/metabolism , Mice , Mice, Mutant Strains , Molecular Structure , PPAR alpha/metabolism , PPAR gamma/metabolism , Protein Conformation , Stereoisomerism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Amides/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Subject(s)
Anabolic Agents/chemical synthesis , Imidazoles/chemical synthesis , Muscle, Skeletal/drug effects , Pyrroles/chemical synthesis , Receptors, Androgen/metabolism , Administration, Oral , Anabolic Agents/pharmacokinetics , Anabolic Agents/pharmacology , Animals , Biological Availability , Crystallography, X-Ray , Half-Life , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Models, Molecular , Muscle, Skeletal/anatomy & histology , Orchiectomy , Prostate/anatomy & histology , Prostate/drug effects , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Subject(s)
Dipeptides/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Evaluation, Preclinical , Humans , Nitriles/chemistry , Nitriles/pharmacology , Structure-Activity RelationshipABSTRACT
Alkyl quinolone molecules 2-heptyl-4-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) are important quorum sensing signals, which play a mediatory role in the pathogenesis of acute and chronic Pseudomonas aeruginosa infection. A targeted approach inhibiting the bacterial 'multiple virulence factor regulon' (MvfR) protein complex, offers the possibility to block the synthesis of MvfR-dependant signal molecules. Here, a high throughput bioanalytical method was developed using LC-MS/MS detection for the selective determination of HHQ and PQS in mouse tissue homogenate, over a sensitive range of 1-5000 and 10-5000pg/mL, respectively. Chromatographic peak distortion of the iron chelator PQS was overcome with the applied use of a bidentate chelator mobile phase additive 2-Picolinic acid at 0.2mM concentration, giving an improved separation and response for the analyte, whilst maintaining overall MS system robustness. Following thigh infection with P. aeruginosa strain 2-PA14 in mice, the concentration and time course of HHQ and PQS (4-hydroxy-2-alkyl-quinolone (HAQ) biomarkers) residing in the biophase were evaluated, and exhibited a low level combined with a substantial inter-individual variability. Quantifiable levels could be obtained from approximately 15h post infection, to the study termination at 21-22h. A dose dependant reduction in HAQ tissue concentrations at selected time points were obtained following MvfR inhibitor administration versus drug vehicle (p<0.01, Kruskal-Wallis-one way ANOVA) and meta -analyses of several studies enabled an inhibitory concentration (IC50) of 80nM free drug to be determined. However, due to the experimental limitations a defined time profile for in-vivo HAQ production could not be characterised. Microsomal stability measurements demonstrated a rapid metabolic clearance of both alkyl quinolone biomarkers in the bacterial host, with a hepatic extraction ratio greater than 0.96 (the measurable assay limit). High clearance underpinned the low concentrations present in the well-perfused thigh tissue. Along with method development and validation details, this paper considers the kinetics of in-vivo HAQ bio-synthesis during Pseudomonas infection; and risks of biomarker over-estimation from samples which contain an exogenous population of bacteria.
Subject(s)
4-Quinolones/analysis , Pseudomonas Infections , Pseudomonas aeruginosa/chemistry , Quorum Sensing , Tandem Mass Spectrometry/methods , 4-Quinolones/metabolism , Animals , Chromatography, Liquid/methods , Humans , Mice , Muscle, Skeletal/chemistry , Muscle, Skeletal/metabolism , Muscle, Skeletal/microbiology , Pseudomonas Infections/metabolism , Pseudomonas aeruginosa/metabolism , Quorum Sensing/physiologyABSTRACT
Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.
Subject(s)
Polypharmacology , Pseudomonas aeruginosa/genetics , Regulon/drug effects , Drug Tolerance , Enzyme Inhibitors/pharmacology , Molecular Targeted Therapy/methods , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/enzymology , Virulence/drug effects , Virulence FactorsABSTRACT
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
ABSTRACT
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/pharmacology , Endothelin A Receptor Antagonists , Isoxazoles/chemistry , Isoxazoles/pharmacology , Receptor, Angiotensin, Type 1/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Biological Availability , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Dogs , Humans , Hypertension/drug therapy , Irbesartan , Isoxazoles/pharmacokinetics , Macaca fascicularis , Male , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Tetrazoles/chemistry , Tetrazoles/pharmacologyABSTRACT
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Pyrroles/chemistry , Pyrroles/pharmacology , Acetamides/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Catalytic Domain , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Glucose Tolerance Test , Humans , Male , Mice , Models, Molecular , Pyrroles/chemical synthesis , Substrate SpecificityABSTRACT
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents/chemical synthesis , Imidazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Catalytic Domain , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Mice , Mice, Obese , Models, Molecular , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Sodium Channel Blockers/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.