- Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI
-
Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.
- Pero, Joseph E.,Rossi, Michael A.,Kelly, Michael J.,Lehman, Hannah D. G. F.,Layton, Mark E.,Garbaccio, Robert M.,O'Brien, Julie A.,Magliaro, Brian C.,Uslaner, Jason M.,Huszar, Sarah L.,Fillgrove, Kerry L.,Tang, Cuyue,Kuo, Yuhsin,Joyce, Leo A.,Sherer, Edward C.,Jacobson, Marlene A.
-
-
Read Online
- 6-HETEROARYLOXY BENZIMIDAZOLES AND AZABENZIMIDAZOLES AS JAK2 INHIBITORS
-
The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2.
- -
-
Paragraph 0185
(2021/11/13)
-
- BENZIMIDAZOLE DERIVATIVES AND AZA-BENZIMIDAZOLE DERIVATIVES AS JANUS KINASE 2 INHIBITORS AND USES THEREOF
-
The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., Janus kinase (JAK), e.g., Janus kinase 2 (JAK2)) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating a disease (e.g., proliferative disease) in a subject in need thereof).
- -
-
Paragraph 00225; 00243
(2020/06/01)
-
- COMBINATIONS COMPRISING BENZODIOXOL AS GLP-1R AGONISTS FOR USE IN THE TREATMENT OF NASH/NAFLD AND RELATED DISEASES
-
In part, the invention provides a new combination comprising (1) a GLP-1R agonist and (2) an ACC inhibitor or a DGAT2 inhibitor, or a KHK inhibitor or FXR agonist. The invention further provides new methods for treating diseases and disorders, for example, fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes, for example, using the new combination described herein.
- -
-
Page/Page column 149; 150
(2020/12/07)
-
- GLP-1 Receptor Agonists and Uses Thereof
-
Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, and 7-aza-benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.
- -
-
Paragraph 0493; 0494
(2020/01/04)
-
- GLP-1 RECEPTOR AGONISTS AND USES THEREOF
-
Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, and 7-aza- benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.
- -
-
Page/Page column 85
(2020/01/08)
-
- Sulfide Analogues of Flupirtine and Retigabine with Nanomolar KV7.2/KV7.3 Channel Opening Activity
-
The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure–activity relationship studies were performed to evaluate the KV7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50=1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.
- Bock, Christian,Surur, Abdrrahman S.,Beirow, Kristin,Kindermann, Markus K.,Schulig, Lukas,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
-
supporting information
p. 952 - 964
(2019/04/10)
-
- Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators
-
Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug-like leads. In the present retro-metabolic drug design study, a series of 43 compounds were synthesized and characterized with regard to KV7.2/3 opening activity and efficacy. The most active compound 22d displays excellent potency (EC50 = 4 nM) and efficacy (154%) as a KV7.2/3 opener. Limited aqueous solubility hampered toxicity testing at concentrations higher than 63 μM, but this concentration was nontoxic to two hepatocellular cell lines (HEP-G2 and TAMH) in culture. The slightly less active but more soluble compound 25b (EC50 = 11 nM, efficacy 111%) showed an improved toxicity/activity ratio compared to flupirtine by three orders of magnitude and represents an attractive lead structure for the development of safer analgesics and antiepileptics.
- Surur, Abdrrahman S.,Bock, Christian,Beirow, Kristin,Wurm, Konrad,Schulig, Lukas,Kindermann, Markus K.,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
-
supporting information
p. 4512 - 4522
(2019/05/17)
-
- Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on KV7.2/KV7.3 Channel Opening Activity
-
Neuronal voltage-gated potassium channels KV7.2/KV7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug-induced liver injury. Thus, safety concerns prevent a broader use of this non-opioid and non-steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers.
- Surur, Abdrrahman S.,Beirow, Kristin,Bock, Christian,Schulig, Lukas,Kindermann, Markus K.,Bodtke, Anja,Siegmund, Werner,Bednarski, Patrick J.,Link, Andreas
-
-
- GLP-1 Agonists and Uses Thereof
-
Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, 7-aza- and 4,7-diaza-benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.
- -
-
Paragraph 0442
(2018/07/05)
-
- Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyridine Derivatives
-
A series of novel imidazo[4,5-b]pyridine derivatives were designed and synthesized. The structures of all the newly synthesized compounds were identified by spectroscopic data NMR, MS, and elemental analysis. Bioassay showed that the compounds exhibited potent fungicidal activities against Erysiphe graminis, Puccinia polysora, and so forth. Particularly, 2-chloro-5-((5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiazole (9b) displayed fungicidal potency against P.?polysora. Its EC50 value: 4.00?mg/L is comparable with that of tebuconazole. The structure–activity relationship for the target compounds is discussed.
- Liu, Minhua,Quan, Chunsheng,Dang, Mingming,Ren, Yeguo,Ren, Jianwei,Xiang, Jun,Liu, Xingping,He, Lian,Liu, Weidong,Liu, Aiping
-
p. 2061 - 2068
(2018/07/31)
-
- NEW IMIDAZO[4,5-B]PYRIDINE DERIVATIVES AS DUAL DYRK1/CLK1 INHIBITORS
-
(Formula I) Compounds of formula (I) usefull for the treatment of cancer, neurodegenerative disorders and metabolic disorders.
- -
-
Page/Page column 31
(2017/05/07)
-
- Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis
-
Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic invest
- Layton, Mark E.,Reif, Alexander J.,Hartingh, Timothy J.,Rodzinak, Kevin,Dudkin, Vadim,Wang, Cheng,Arrington, Ken,Kelly, Michael J.,Garbaccio, Robert M.,O'Brien, Julie A.,Magliaro, Brian C.,Uslaner, Jason M.,Huszar, Sarah L.,Fillgrove, Kerry L.,Tang, Cuyue,Kuo, Yuhsin,Jacobson, Marlene A.
-
supporting information
p. 1260 - 1264
(2016/02/23)
-
- Synthesis and Insecticidal Activity of Novel Nitropyridyl-Based Dichloropropene Ethers
-
Dihalopropene ether insecticides are known for good features such as no cross-resistance to other insecticide classes and safety for mammals. Pyridalyl is the only currently commercialized dichloropropene ether insecticide; however, it contains a trifluoromethyl group, the synthesis of which requires harsh reagents and reaction conditions. To search for novel dihalopropene ethers with unique biological activities but without trifluoromethyl groups, a series of nitropyridyl-based dichloropropene ether analogues were synthesized by reacting nitro-based halopyridine with 2,6-dichloro-4-(3,3-dichloroallyloxy)phenol or 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-hydroxypropyl ether. Bioassay showed that the compounds exhibited potent insecticidal activities against various lepidopteran pests. Particularly, 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-(5-nitro-2-pyridyloxy)propyl ether (8e) was active against major agricultural pests, and its insecticidal potency was comparable to that of Pyridalyl. Besides the trifluoromethyl group in Pyridalyl, a nitro group on the 5-position of the pyridyl ring is also viable for the development of optimal insecticidal activity.
- Liu, Aiping,Yu, Wanqi,Liu, Minhua,Bai, Jianjun,Liu, Weidong,Liu, Xingping,Pei, Hui,Hu, Li,Huang, Mingzhi,Wang, Xiaoguang
-
p. 7469 - 7475
(2015/09/15)
-
- Pyrazolopyrrolidine Derivatives and their Use in the Treatment of Disease
-
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
- -
-
Paragraph 1013; 1014
(2014/12/09)
-
- PYRAZOLOPYRROLIDINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF DISEASE
-
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
- -
-
Page/Page column 209
(2014/12/12)
-
- PRMT5 INHIBITORS AND USES THEREOF
-
Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described
- -
-
Paragraph 00394
(2014/07/08)
-
- Design and synthesis of novel DFG-Out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds
-
To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.
- Okaniwa, Masanori,Hirose, Masaaki,Imada, Takashi,Ohashi, Tomohiro,Hayashi, Youko,Miyazaki, Tohru,Arita, Takeo,Yabuki, Masato,Kakoi, Kazuyo,Kato, Juran,Takagi, Terufumi,Kawamoto, Tomohiro,Yao, Shuhei,Sumita, Akihiko,Tsutsumi, Shunichirou,Tottori, Tsuneaki,Oki, Hideyuki,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
-
experimental part
p. 3452 - 3478
(2012/06/17)
-
- IMIDAZOPYRIDIN-2-ONE DERIVATIVES
-
The present invention is directed to imidazopyridin-2-one derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.
- -
-
Page/Page column 22
(2013/02/28)
-
- POSITIVE ALLOSTERIC MODULATORS OF MGLUR2
-
The present invention is directed to 5-substituted 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and 1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2,-dioxide derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved
- -
-
Page/Page column 76
(2011/10/03)
-
- POSITIVE ALLOSTERIC MODULATORS OF MGLUR2
-
The present invention is directed to 5-substituted 1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one derivatives which are positive allosteric modulators of the mGluR2 receptor, useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 receptor is involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved, such as schizophrenia.
- -
-
Page/Page column 25
(2012/01/05)
-
- IMIDAZOPYRIDIN-2-ONE DERIVATIVES
-
The present invention is directed to imidazopyridin-2-one derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.
- -
-
Page/Page column 23
(2011/04/19)
-
- AMINOPIPERIDINES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
-
The present invention is directed to novel substituted aminopiperidines which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DPP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
- -
-
Page/Page column 35; 51
(2010/10/20)
-
- Inhibitors of glycogen synthase kinase 3
-
New pyrimidine or pyridine based compounds, compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and of treatment of GSK3 mediated disorders in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of disorders mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.
- -
-
-
- Molecular design, synthesis, and hypoglycemic activity of a series of thiazolidine-2,4-diones
-
A series of imidazopyridine thiazolidine-2,4-diones were designed and synthesized from their corresponding pyridines. These compounds represent conformationally restricted analogues of the novel hypoglycemic compound rosiglitazone (5). The series was evaluated for its effect on insulin-induced 3T3-L1 adipocyte differentiation in vitro and its hypoglycemic activity in the genetically diabetic KK mouse in vivo. The structure-activity relationships are discussed. On the basis of the in vivo potency, 5-[4-(5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)ben zyl]thiazolidine-2,4-dione (19a) was selected as the candidate for further studies in a clinical setting.
- Oguchi,Wada,Honma,Tanaka,Kaneko,Sakakibara,Ohsumi,Serizawa,Fujiwara,Horikoshi,Fujita
-
p. 3052 - 3066
(2007/10/03)
-
- Heterocyclic compounds having anti-diabetic activity and their use
-
Compounds of formula (I): STR1 [wherein: X represents an unsubstituted or substituted indolyl, indolinyl, azaindolyl, azaindolinyl, imidazopyridyl or imidazopyrimidinyl group; Y represents an oxygen or sulfur atom; Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group; R represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a hydroxy group, a nitro group, an aralkyl group or a unsubstituted or substituted amino group; and m is an integer of from 1 to 5] have hypoglycemic and anti-diabetic activities.
- -
-
-
- Compounds with antiulcer and antisecretory activity. III. N-substituted imidazolones condensed with nitrogen-containing heteroaromatic rings
-
The syntheses of imidazo[4,5-b]pyridin-2-ones and -thiones, imidazo [4,5-c]pyridin-2-ones and 7,9-dihydro-8H-purin-8-ones arylated (or heteroarylated) at an imidazolone nitrogen are reported. Only some compounds of the first series have marked antisecreto
- Bianchi,Butti,Rossi,et al.
-
p. 501 - 506
(2007/10/02)
-
