ABSTRACT
A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a-e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a-e showed CRF1 receptor binding activity with IC50 values of less than 400â¯nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50â¯=â¯7.1â¯nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R, which exhibited potent CRF1 receptor binding activity (IC50â¯=â¯58â¯nM) with good oral bioavailability (Fâ¯=â¯68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10â¯mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10â¯mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies.
Subject(s)
Benzimidazoles/pharmacology , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Brain/metabolism , CHO Cells , Cricetulus , Cyclization , Drug Design , Humans , Male , Microsomes, Liver/metabolism , Molecular Conformation , Molecular Docking Simulation , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats, Wistar , Receptors, Corticotropin-Releasing Hormone/chemistry , StereoisomerismABSTRACT
Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50=9.5nM) and in vitro antagonistic activity (IC50=88nM) but is rapidly metabolized by human hepatic microsomes (182µL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87µL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC50=4.1nM), in vitro antagonistic activity (IC50=44nM), and slow dissociation from the CRF1 receptor. Orally administered compound 24d (6-24µmol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d.
Subject(s)
Benzimidazoles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetulus , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Wistar , Sheep , Structure-Activity RelationshipABSTRACT
On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC50 = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.
Subject(s)
Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrimidinones/pharmacology , Thiophenes/pharmacology , Triazoles/pharmacology , Zinc/chemistry , Animals , Cartilage/metabolism , Cattle , Chelating Agents/chemical synthesis , Chelating Agents/pharmacology , Collagen/metabolism , Drug Design , Matrix Metalloproteinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidinones/chemical synthesis , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Thiophenes/chemical synthesis , Triazoles/chemical synthesisABSTRACT
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1' binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.
Subject(s)
Amides/pharmacology , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Quinazolinones/pharmacology , Triazoles/pharmacology , Zinc/chemistry , ADAM17 Protein/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Drug Design , Humans , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Microsomes, Liver/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Quinazolinones/chemical synthesis , Quinazolinones/pharmacokinetics , Rats , Triazoles/chemical synthesis , Triazoles/pharmacokineticsABSTRACT
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50=27nM, 56nM, respectively). This compound exhibited ex vivo (125)I-Tyr(0) ((125)I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure-activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Amination , Animals , Drug Discovery , Humans , Mice , Models, Molecular , Receptors, Corticotropin-Releasing Hormone/metabolismABSTRACT
Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 µM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 µmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.
Subject(s)
Benzimidazoles/antagonists & inhibitors , Benzimidazoles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Adrenocorticotropic Hormone/metabolism , Animals , Brain Chemistry/drug effects , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Hypothalamo-Hypophyseal System/drug effects , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Structure-Activity RelationshipABSTRACT
To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.
Subject(s)
Anabolic Agents/chemical synthesis , Androgens/chemical synthesis , Naphthols/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Androgen/metabolism , Anabolic Agents/pharmacology , Androgens/pharmacology , Animals , Castration , Central Nervous System/drug effects , Central Nervous System/metabolism , Gene Expression , Humans , Male , Molecular Docking Simulation , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Naphthols/pharmacology , Prostate/drug effects , Prostate/metabolism , Protein Binding , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Androgen/genetics , Sexual Behavior, Animal/drug effects , Structure-Activity Relationship , Testosterone/pharmacologyABSTRACT
On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1â³ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.
Subject(s)
Benzene Derivatives/chemistry , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase Inhibitors/administration & dosage , Matrix Metalloproteinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Benzene Derivatives/administration & dosage , Benzene Derivatives/pharmacology , Binding Sites/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Matrix Metalloproteinase Inhibitors/chemistry , Models, Molecular , Molecular Structure , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.
Subject(s)
Benzoates/chemical synthesis , Benzoates/pharmacology , Matrix Metalloproteinase 13/drug effects , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Benzoates/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Osteoarthritis/drug therapy , Quinazolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.
Subject(s)
Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Azepines/pharmacology , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/pharmacology , Drug Design , Motor Activity/drug effects , Administration, Oral , Animals , Antidepressive Agents/administration & dosage , Azepines/administration & dosage , Azepines/chemistry , Depression/drug therapy , Dopamine Uptake Inhibitors/administration & dosage , Dose-Response Relationship, Drug , Humans , Ligands , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 ± 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.
Subject(s)
Antipsychotic Agents/chemical synthesis , Benzamides/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Thiophenes/chemical synthesis , Administration, Oral , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Brain/metabolism , CHO Cells , Cricetulus , Humans , Male , Methamphetamine/pharmacology , Mice, Inbred ICR , Models, Molecular , Motor Activity/drug effects , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacologyABSTRACT
A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW < ca. 300), low aromatic ring count (number = 1) and reduced lipophilicity (ClogP < 3.5) were hypothesized to be key factors to avoid the CAD associated liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.
Subject(s)
Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Male , Mice , Mice, Inbred ICR , Models, Molecular , Neurotransmitter Uptake Inhibitors/chemical synthesis , Piperidines/chemistry , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Structure-Activity RelationshipABSTRACT
We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Prostatic Neoplasms/drug therapy , Pyrrolidines/chemistry , Pyrrolidines/therapeutic use , Animals , Castration , Cell Line, Tumor , Drug Design , Humans , Male , Mice , Models, Molecular , Prostate/drug effects , Prostate/metabolism , Prostate/surgery , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/surgery , Receptors, Androgen/metabolism , Xenograft Model Antitumor AssaysABSTRACT
G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic ß-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 µM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to ß-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.
Subject(s)
Benzofurans/pharmacology , Glucose/pharmacology , Insulin/metabolism , Receptors, G-Protein-Coupled/agonists , Sulfones/pharmacology , Animals , Benzofurans/chemical synthesis , Benzofurans/pharmacokinetics , Diabetes Mellitus, Type 2/drug therapy , Female , Glucose Tolerance Test , Hep G2 Cells , Humans , Insulin Secretion , Male , Rats , Receptors, G-Protein-Coupled/drug effects , Stereoisomerism , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
Subject(s)
Androgen Receptor Antagonists/chemical synthesis , Drug Design , Pyrazoles/chemistry , Receptors, Androgen/chemistry , Administration, Oral , Androgen Receptor Antagonists/pharmacology , Androgen Receptor Antagonists/therapeutic use , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Mice , Mice, Nude , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/drug therapy , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Androgen/metabolism , Transplantation, HeterologousABSTRACT
As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
Subject(s)
Cyclic S-Oxides/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , CHO Cells , Calcium/metabolism , Caspases/metabolism , Cell Survival , Cricetinae , Cyclic S-Oxides/pharmacokinetics , Cyclic S-Oxides/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Female , Glucose Intolerance/drug therapy , Hep G2 Cells , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Inhibitory Concentration 50 , Male , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Rats , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to ß-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
Subject(s)
Acetates/chemical synthesis , Acids, Acyclic/chemical synthesis , Benzofurans/chemical synthesis , Insulin/blood , Receptors, G-Protein-Coupled/agonists , Acetates/pharmacokinetics , Acetates/pharmacology , Acids, Acyclic/pharmacokinetics , Acids, Acyclic/pharmacology , Animals , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , CHO Cells , Cricetinae , Cricetulus , Female , Glucose Intolerance/metabolism , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin Secretion , Models, Molecular , Protein Binding , Rats , Rats, Wistar , Species SpecificityABSTRACT
A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
Subject(s)
Androgen Receptor Antagonists/chemical synthesis , Antineoplastic Agents/chemical synthesis , Drug Design , Pyrroles/chemistry , Receptors, Androgen/chemistry , Amino Acid Substitution , Androgen Receptor Antagonists/pharmacology , Androgen Receptor Antagonists/therapeutic use , Androgen Receptor Antagonists/toxicity , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Male , Mice , Mice, Inbred ICR , Mice, Nude , Mutation , Prostatic Neoplasms/drug therapy , Pyrroles/pharmacology , Pyrroles/therapeutic use , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Transplantation, HeterologousABSTRACT
A new class of pyrrolo[2,3-d]pyrimidin-4-one corticotropin-releasing factor 1 (CRF(1)) receptor antagonists has been designed and synthesized. In general, reported CRF(1) receptor antagonists possess a sp(2)-nitrogen atom as hydrogen bonding acceptor (HBA) on their core scaffolds. We proposed to use a carbonyl group of pyrrolo[2,3-d]pyrimidin-4-one derivatives as a replacement for the sp(2)-nitrogen atom as HBA in classical CRF(1) receptor antagonists. As a result, several pyrrolo[2,3-d]pyrimidin-4-one derivatives showed CRF(1) receptor binding affinity with IC(50) values in the submicromolar range. Ex vivo (125)I-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (16b) (30 mg/kg, p.o.) was able to penetrate into the brain and inhibit radioligand binding to CRF(1) receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3-d]pyrimidin-4-one derivatives as the first CRF(1) antagonists with a carbonyl-based HBA.
Subject(s)
Pyrimidines/chemistry , Pyrroles/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Brain/metabolism , Drug Evaluation, Preclinical , Hydrogen Bonding , Ketones/chemistry , Mice , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolismABSTRACT
G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic ß-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.