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1.
Bioorg Med Chem ; 85: 117273, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37030194

ABSTRACT

GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.


Subject(s)
Blood Glucose , Hyperglycemia , Rats , Animals , Receptors, G-Protein-Coupled , Glucagon-Like Peptide 1 , Hypoglycemic Agents/pharmacology , Pyrrolidines/pharmacology , Pyrrolidines/chemistry , Insulin
2.
J Med Chem ; 65(5): 4291-4317, 2022 03 10.
Article in English | MEDLINE | ID: mdl-35179904

ABSTRACT

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.


Subject(s)
Azetidines , Diabetes Mellitus, Type 2 , Hypoglycemia , Organophosphonates , Azetidines/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucokinase , Humans , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Organophosphonates/pharmacology , Organophosphonates/therapeutic use
3.
Blood Adv ; 6(1): 108-120, 2022 01 11.
Article in English | MEDLINE | ID: mdl-34625796

ABSTRACT

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes BM dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC after HSCT, a hypothesis that could explain morbidity noted after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have also identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and are accentuated by or develop specifically after myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets, including mesenchymal lineage cells, macrophages, and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.


Subject(s)
Bone Marrow , Hematopoietic Stem Cell Transplantation , Proteins , Shwachman-Diamond Syndrome , Animals , Bone Marrow/metabolism , Endothelial Cells , Gene Deletion , Hematopoiesis/genetics , Humans , Mice , Proteins/genetics , Proteins/metabolism , Shwachman-Diamond Syndrome/genetics , Shwachman-Diamond Syndrome/surgery , Transplantation Conditioning
5.
J Med Chem ; 61(3): 681-694, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29316397

ABSTRACT

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.


Subject(s)
Drug Discovery , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biological Availability , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrrolidines/chemistry
6.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28112924

ABSTRACT

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Subject(s)
Hypoglycemic Agents/pharmacology , Pyrrolidines/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Cell Line , Cells, Cultured , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide 1/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Male , Mice, Inbred C57BL , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Receptors, G-Protein-Coupled/metabolism
7.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Article in English | MEDLINE | ID: mdl-27326332

ABSTRACT

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.

8.
Bioorg Med Chem Lett ; 25(6): 1196-205, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25686852

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/blood
9.
Bioorg Med Chem Lett ; 21(22): 6693-8, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21983444

ABSTRACT

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Animals , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Enzyme Inhibitors/pharmacokinetics , Humans , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred BALB C , Structure-Activity Relationship
10.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Article in English | MEDLINE | ID: mdl-20218621

ABSTRACT

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.


Subject(s)
Drug Discovery , Glycine/analogs & derivatives , Oxazoles/chemistry , Oxazoles/pharmacology , PPAR alpha/agonists , Animals , Cell Line , Cricetinae , Crystallography, X-Ray , Drug-Related Side Effects and Adverse Reactions , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Glycine/toxicity , Humans , Male , Mice , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/toxicity , PPAR alpha/chemistry , PPAR alpha/genetics , Protein Structure, Tertiary , Substrate Specificity , Transcriptional Activation/drug effects
11.
Bioorg Med Chem Lett ; 19(5): 1451-6, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19201606

ABSTRACT

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 Relationship
12.
Bioorg Med Chem Lett ; 18(6): 1939-44, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18291645

ABSTRACT

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/blood
13.
J Pharmacol Exp Ther ; 324(2): 576-86, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17986646

ABSTRACT

Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED(50) for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.


Subject(s)
Guinea Pigs/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Models, Animal , Animals , Cells, Cultured , Drug Evaluation, Preclinical/methods , Guinea Pigs/blood , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Rats , Rats, Sprague-Dawley
14.
J Pharmacol Exp Ther ; 321(1): 107-15, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17259449

ABSTRACT

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Glycine/analogs & derivatives , Hypoglycemic Agents/pharmacology , Oxazoles/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Body Weight/drug effects , C-Peptide/metabolism , Diabetes Mellitus, Experimental/genetics , Disease Progression , Fatty Acids, Nonesterified/blood , Female , Glucose Tolerance Test , Glycated Hemoglobin/metabolism , Glycine/pharmacology , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Pancreas/drug effects , Pancreas/metabolism , Triglycerides/blood
15.
Diabetes ; 55(1): 240-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16380499

ABSTRACT

Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glycine/analogs & derivatives , Hypoglycemic Agents/therapeutic use , Insulin-Secreting Cells/drug effects , Oxazoles/therapeutic use , Peroxisome Proliferator-Activated Receptors/agonists , Adiponectin/blood , Animals , Blood Glucose/drug effects , Corticosterone/blood , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diet , Female , Glycine/pharmacology , Glycine/therapeutic use , Hyperlipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Insulin/blood , Insulin-Secreting Cells/metabolism , Liver , Mice , Obesity , Oxazoles/pharmacology , Peroxisome Proliferator-Activated Receptors/metabolism , Rosiglitazone , Thiazolidinediones/therapeutic use
16.
Bioorg Med Chem Lett ; 14(20): 5067-70, 2004 Oct 18.
Article in English | MEDLINE | ID: mdl-15380200

ABSTRACT

5-Carboxamido-1,3,2-dioxaphosphorinanes have been identified as potent inhibitors of microsomal triglyceride-transfer protein. The 1,3,2-dioxaphosphorine functionality acted as a neutral and stable replacement for piperidine and piperidine N-oxide.


Subject(s)
Amides/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Cyclic P-Oxides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cricetinae , Cyclic P-Oxides/chemistry , Cyclic P-Oxides/pharmacology , Humans , In Vitro Techniques , Male , Stereoisomerism , Structure-Activity Relationship
17.
Bioorg Med Chem Lett ; 13(7): 1337-40, 2003 Apr 07.
Article in English | MEDLINE | ID: mdl-12657277

ABSTRACT

A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.


Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Carrier Proteins/antagonists & inhibitors , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Animals , Cholesterol, VLDL/metabolism , Cricetinae , Drug Design , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Rats , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured
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