ABSTRACT
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
ABSTRACT
GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.
ABSTRACT
MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Subject(s)
Carbolines/chemistry , Carbolines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Carbolines/chemical synthesis , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Humans , Molecular Structure , RatsABSTRACT
The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).
ABSTRACT
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Subject(s)
Amines/pharmacology , Enzyme Inhibitors/pharmacology , Factor IXa/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/chemistry , Animals , Biological Availability , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Factor IXa/metabolism , Humans , Models, Molecular , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
ABSTRACT
A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents.
ABSTRACT
A structure-activity relationship study of the imidazolyl-ß-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.
ABSTRACT
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Subject(s)
Piperazines/chemistry , Receptor, Melanocortin, Type 4/agonists , Urea/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Eating/drug effects , Haplorhini , Mice , Obesity/drug therapy , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacokinetics , Urea/therapeutic useABSTRACT
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Subject(s)
Obesity/drug therapy , Receptor, Melanocortin, Type 4/agonists , Triazoles/pharmacology , Animals , Chromatography, High Pressure Liquid , Disease Models, Animal , Mice , Mice, Knockout , Molecular Structure , Rats , Receptor, Melanocortin, Type 4/genetics , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Subject(s)
Ligands , Receptor, Melanocortin, Type 4/agonists , Animals , Humans , Piperazine , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Subject(s)
Piperidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Animals , Brain/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Subject(s)
Amides/chemistry , Anti-Obesity Agents/chemistry , Obesity/drug therapy , Pyrrolidines/chemistry , Receptor, Melanocortin, Type 4/agonists , Spiro Compounds/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Body Weight/drug effects , Humans , Mice , Mice, Knockout , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Subject(s)
Erectile Dysfunction/drug therapy , Indans/chemistry , Indans/therapeutic use , Receptor, Melanocortin, Type 4/agonists , Receptor, Melanocortin, Type 4/metabolism , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Haplorhini , Humans , Indans/pharmacokinetics , Indans/pharmacology , Male , Mice , Molecular Structure , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Receptor, Melanocortin, Type 4/agonists , Administration, Oral , Humans , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , TelomeraseABSTRACT
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Subject(s)
Estrogen Receptor alpha/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacokinetics , Breast Neoplasms/drug therapy , Cell Line, Tumor , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Female , Humans , Inhibitory Concentration 50 , Ligands , Uterus/drug effectsABSTRACT
A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM.
Subject(s)
Receptors, Chemokine/antagonists & inhibitors , Animals , CHO Cells , Chemokine CCL2/antagonists & inhibitors , Chemokine CCL2/metabolism , Chemotaxis/drug effects , Chromatography, High Pressure Liquid , Cricetinae , Cricetulus , Dogs , Drug Design , Humans , In Vitro Techniques , Indicators and Reagents , Membranes/metabolism , Monocytes/drug effects , Monocytes/metabolism , Neurokinin-1 Receptor Antagonists , Rats , Rats, Sprague-Dawley , Receptors, CCR2 , Receptors, Chemokine/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
Subject(s)
Glycine/analogs & derivatives , Monocytes/drug effects , Receptors, Chemokine/antagonists & inhibitors , Animals , Binding Sites , CHO Cells/drug effects , Calcium/metabolism , Chemokine CCL2/antagonists & inhibitors , Chemokine CCL2/metabolism , Cricetinae , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Inhibitory Concentration 50 , Models, Biological , Receptors, CCR2 , Receptors, Chemokine/metabolismABSTRACT
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.