- Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein
-
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive therapeutic target for human cancers and other human diseases. Herein, we report our discovery of potent small-molecule SHP2 degraders whose design is based upon the proteolysis-targeting chimera (PROTAC) concept. This work has led to the discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. SHP2-D26 achieves DC50 values of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that induced SHP2 degradation is a very effective approach to inhibit the function of SHP2. Further optimization of these SHP2 degraders may lead to the development of a new class of therapies for cancers and other human diseases.
- Wang, Mingliang,Lu, Jianfeng,Wang, Mi,Yang, Chao-Yie,Wang, Shaomeng
-
-
Read Online
- Discovery and characterization of a potent and selective EP4 receptor antagonist
-
Abstract EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα prod
- Schiffler, Matthew A.,Chandrasekhar, Srinivasan,Fisher, Matthew J.,Harvey, Anita,Kuklish, Steven L.,Wang, Xu-Shan,Warshawsky, Alan M.,York, Jeremy S.,Yu, Xiao-Peng
-
-
Read Online
- BRM TARGETING COMPOUNDS AND METHODS OF USE THEREOF
-
The present invention relates to bifunctional compounds comprising a binding fraction to a target protein and a binding fraction to ubiquitin ligase E3, and associated methods of use.
- -
-
Paragraph 0492; 0495
(2021/12/31)
-
- TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 0337
(2021/02/12)
-
- SUBSTITUTED PYRAZOLE COMPOUNDS AS TOLL RECEPTOR INHIBITORS
-
Disclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein G, A, R1, and R5 are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.
- -
-
Page/Page column 232-233
(2021/05/07)
-
- Aptamer-PROTAC Conjugates (APCs) for Tumor-Specific Targeting in Breast Cancer
-
Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.
- Dong, Guoqiang,Gao, Fei,He, Shipeng,Ma, Haoqian,Ma, Junhui,Sheng, Chunquan
-
supporting information
p. 23299 - 23305
(2021/08/13)
-
- GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
-
The invention provides a GPX4 protein degradation agent, a preparation method thereof, and an anti-tumor cell drug, and belongs to the technical field of drug application. The GPX4 protein degradation agent provided by the invention has a protein degradation targeting chimera (PROTAC) molecular structure, a mother nucleus structure of the GPX4 protein degradation agent is used as a small molecule ligand for combining target protein, an A2 substituent is used as a small molecule ligand for combining an E3 ubiquitin ligase compound, and an A1 substituent is used as a connecting group for connecting the two ligands. The GPX4 protein degradation agent with the structure can specifically recognize GPX4 protein and effectively ubiquitinate and degrade the GPX4 protein, so that tumor cell ferroptosis is induced.
- -
-
Paragraph 0317-0320
(2021/09/04)
-
- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 1 PROTEINS
-
The present invention relates to compounds comprising an interleukin-1 receptor-associated kinase 1 (IRAK1) protein binding moiety and a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety, and associated methods of use. The compounds are useful as modulators of targeted ubiquitination, especially with respect to IRAK1, which is degraded by the compounds according to the invention.
- -
-
Page/Page column 56; 57
(2021/02/05)
-
- SMARCA2-VHL DEGRADERS
-
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.
- -
-
Page/Page column 40
(2021/07/17)
-
- COMPOUNDS AND METHODS FOR TARGETED DEGRADATION OF KRAS
-
Bifunctional compounds, which find utility as modulators of Kirsten ras sarcoma protein (KRas or KRAS), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the Von Hippel-Lindau E3 ubiquitin ligase and on the other end a moiety which binds KRas, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 00237
(2021/10/15)
-
- BI-FUNCTIONAL COMPOUNDS AND METHODS FOR TARGETED UBIQUITINATION OF ANDROGEN RECEPTOR
-
The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.
- -
-
Paragraph 00162
(2021/11/26)
-
- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
-
The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
- -
-
Paragraph 0873; 0874; 0875
(2020/05/21)
-
- BI-FUNCTIONAL COMPOUNDS AND METHODS FOR TARGETED UBIQUITINATION OF ANDROGEN RECEPTOR
-
The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.
- -
-
Paragraph 0127
(2020/08/19)
-
- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
-
The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 1059; 1060
(2020/03/29)
-
- ESTROGEN RECEPTOR PROTEIN DEGRADERS
-
The present disclosure provides compounds represented by Formula (I): A-L-B and the salts or solvates thereof, wherein A, L, and B are as defined in the specification. Compounds having Formula I are estrogen receptor degraders useful for the treatment of
- -
-
Paragraph 0180
(2020/07/21)
-
- AMIDE COMPOUND HAVING BET PROTEOLYSIS-INDUCING ACTION AND MEDICINAL APPLICATION THEREOF
-
The present invention aims to provide a compound that: has an excellent cytotoxic action on cancer cells, excellent induction of BET protein degradation in cancer cells, and an excellent binding-inhibiting action on BET protein and acetylated histone; and is effective as an anti-cancer agent, a BET protein degradation-inducing agent, or a BET protein inhibiting agent. A compound indicated in general formula (I) or a pharmacologically acceptable salt thereof. {In the formula, each symbol is as outlined in the Description.}
- -
-
Paragraph 0228-0230
(2020/01/31)
-
- BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 1043-1045
(2019/10/23)
-
- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
-
The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
- -
-
Page/Page column 83-84
(2019/11/12)
-
- Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer
-
We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.
- Han, Xin,Wang, Chao,Qin, Chong,Xiang, Weiguo,Fernandez-Salas, Ester,Yang, Chao-Yie,Wang, Mi,Zhao, Lijie,Xu, Tianfeng,Chinnaswamy, Krishnapriya,Delproposto, James,Stuckey, Jeanne,Wang, Shaomeng
-
supporting information
p. 941 - 964
(2019/01/21)
-
- Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)
-
The estrogen receptor (ER) is a validated target for the treatment of estrogen receptor-positive (ER+) breast cancer. Here, we describe the design, synthesis, and extensive structure-activity relationship (SAR) studies of small-molecule ERα degraders base
- Hu, Jiantao,Hu, Biao,Wang, Mingliang,Xu, Fuming,Miao, Bukeyan,Yang, Chao-Yie,Wang, Mi,Liu, Zhaomin,Hayes, Daniel F.,Chinnaswamy, Krishnapriya,Delproposto, James,Stuckey, Jeanne,Wang, Shaomeng
-
p. 1420 - 1442
(2019/01/30)
-
- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 00475-00476
(2019/10/29)
-
- INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
-
The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.
- -
-
Paragraph 0333-0336
(2018/04/21)
-
- MODULATORS OF ESTROGEN RECEPTOR PROTEOLYSIS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 00538; 00539; 00540; 00541
(2018/08/20)
-
- TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 0613-0615
(2018/05/24)
-
- INHIBITORS OF MUTANT ISOCITRATE DEHYDROGENASES AND COMPOSITIONS AND METHODS THEREOF
-
The invention provides novel chemical compounds useful for treating cancer, or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.
- -
-
Paragraph 00129; 00136; 00213; 00220
(2018/07/29)
-
- ISOQUINOLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
A compound of formula (I): wherein the substituents are as defined in the description. Medicinal products containing the same which are useful in treating or preventing pathologies which are the result of activation of the RhoA/ROCK pathway and phosphorylation of the myosin light chain.
- -
-
Paragraph 0243; 0256; 0257; 0258; 0259; 0608; 0609; 0610
(2017/06/12)
-
- PROTEIN-PROTEIN INTERACTION INDUCING TECHNOLOGY
-
The present disclosure is based on the surprising and unexpected discovery that a ligand molecule with certain characteristics is able to bind to two protein molecules simultaneously and recruit them to form a transient or stable protein-protein interaction complex. The protein-protein interaction and other cross-domain interactions gained in this process contribute additional stabilization energy to the complex beyond the combination of the binary binding energies, and therefore, largely increase the binding potency of the ligand. Accordingly, the present disclosure provides a Protein-Protein Interaction Inducing Technology (PPIIT), which includes a method to design and identify the tripartite or bifunctional compounds and use such compounds to induce protein-protein interactions in various contexts. The present disclosure also provides a composition for the purpose of inducing protein-protein interactions.
- -
-
Paragraph 0200; 0201
(2017/10/17)
-
- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS
-
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
- -
-
Paragraph 00203
(2017/03/21)
-
- AUTOTAXIN INHIBITORY COMPOUNDS
-
The present invention relates to compounds of formula I, wherein A1, A2, A3, R1, R2, R3, R4, R5, R6, L, Ar and Q are each as defined herein. The compounds of the present invention are inhibitors of autotaxin (ATX) enzyme activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions (e.g. fibrosis) in which ATX activity is implicated.
- -
-
Paragraph 00337; 00338
(2016/09/22)
-
- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF THE ANDROGEN RECEPTOR
-
The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.
- -
-
Paragraph 0417; 0418; 0419
(2016/08/17)
-
- HETEROCYCLIC AMIDE DERIVATIVE AND MEDICINE CONTAINING SAME
-
Compound represented by formula (I): wherein each symbol is as defined herein, exhibit TRPA1 antagonist activity, and are useful for the prophylaxis or treatment of diseases involving TRPA1 antagonist and TRPA1.
- -
-
Paragraph 0302; 0303
(2015/10/28)
-
- PHENOXYETHYL PIPERIDINE COMPOUNDS
-
The present invention provides a compound of the Formula II: Formula II wherein X is: R1 is H, -CN, or F; R2 is H or methyl; R3 is H; and R4 is H, methyl, or ethyl; or R3 and R4 joined toge
- -
-
Page/Page column 8
(2014/01/17)
-
- METHODS OF PEST CONTROL IN SOYBEAN
-
The present invention provides methods comprising applying to a crop of soybean plants, the locus thereof, or propagation material thereof, a compound a compound of formula (I) wherein -B1-B2-B3- is -C=N-O-, -C=N-CH2
- -
-
Page/Page column 44
(2014/02/16)
-
- METHODS OF CONTROLLING INSECTS
-
The present invention provides a method comprising applying to a crop of cotton plants, the locus thereof, or propagation material thereof, a compound of formula (I) wherein -B1-B2-B3-is -C=N-O-, -C=N-CH2-, or -
- -
-
Page/Page column 55; 56
(2014/03/25)
-
- METHODS OF CONTROLLING INSECTS
-
The present invention provides a method comprising applying to a crop of rice plants, the locus thereof, or propagation material thereof, a compound of formula (I) wherein -B1-Β2-Β3- is -C=N-O-, -C=N-CH2-, or -N
- -
-
Page/Page column 55
(2014/03/25)
-
- METHODS OF SOIL PEST CONTROL
-
The present invention provides a method of controlling and/or preventing soil-dwelling pests in useful plants comprising applying to the locus of the useful plant or treating propagation material thereof, preferably a seed, with a compound of formula (I),
- -
-
Page/Page column 63
(2014/03/25)
-
- METHODS OF CONTROLLING INSECTS
-
The present invention provides provides a method for controlling and/or preventing insects from the genus of Plutella in useful plants, comprising applying to a crop of useful plants, the locus thereof, or propagation material thereof, a compound of formu
- -
-
Page/Page column 53
(2014/03/25)
-
- New pyrrolidine derivatives, pharmaceutical compositions and uses thereof
-
Pyrrolidine derivatives of the formula and their use as medicaments for the treatment of obesity and type 2 diabetes.
- -
-
Paragraph 0315-0317
(2014/04/18)
-
- NEW PYRROLIDINE DERIVATIVES AND THEIR USE AS ACETYL-COA CARBOXYLASE INHIBITORS
-
The invention relates to new pyrrolidine derivatives of the formula (I) to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.
- -
-
Page/Page column 67; 68
(2014/05/07)
-
- Pyrrolidine derivatives, pharmaceutical compositions and uses thereof
-
The invention relates to new pyrrolidine derivatives of the formula to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.
- -
-
Paragraph 0303; 0304; 0305; 0306; 0307
(2014/08/07)
-
- PYRROLIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
The invention relates to new pyrrolidine derivatives of the formula (I), to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.
- -
-
Page/Page column 75
(2014/08/07)
-
- PYRIMIDINE-SUBSTITUTED PYRROLIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
The invention relates to new pyrrolidine derivatives of the formula wherein R1 to R3, Ar, L T and n are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical
- -
-
Paragraph 0290; 0291; 0292; 0293; 0294
(2014/10/29)
-
- PYRIMIDINE-SUBSTITUTED PYRROLIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
The invention relates to new pyrrolidine derivatives of the formula (I), wherein R1 to R3, Ar, L T and n are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceu
- -
-
Page/Page column 79; 80
(2014/11/11)
-
- NEW AZETIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
The invention relates to new azetidine derivatives of the formula (I) to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.
- -
-
Page/Page column 69
(2013/07/19)
-
- Azetidine Derivatives
-
Azetidine derivatives of which the following is exemplary and their use in the treatment of obesity, diabetes or dyslipidemia.
- -
-
Paragraph 0343; 0344; 0345; 0346; 0352; 0353; 0354; 0355
(2013/07/19)
-
- PYRIDINE AMIDE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
-
The invention relates pyridine amide derivative of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, linear o branched (C1-C3)alkyl or joined together they form a cyclopropyl ring; R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3; A is C or N; E is a group of formula (B) or (C), wherein B is C(O)OH, C(O)O(C1-C3)alkyl, and C is selected from the group consisting of formula (I) m is 1,2 or 3, n is 0 or 1, W is —O—, —O(C1-C3 alkyl)-; —(C1-C3 alkyl)O—; —C(O)—; —C(═N—O(C1-C3 alkyl))-; —NH— or —NH(C1-C3alkyl)-; Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, —NH(C1-C3alkyl)-; —N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom which is covalently bonded to Ar and optionally containing one or two heteroatoms selected from N, O and S; and a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, (C1-C3)alkylcarbonyl. The compounds of the invention could be used for manufacturing a medicament for the treatment of pathologies which require the use of an antagonist of the EP4 receptor, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, endometriosis and migraine.
- -
-
Paragraph 0255-0256
(2013/10/08)
-
- PYRIDINE AMIDE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
-
The invention relates pyridine amide derivative of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, linear o branched (C1-C3)alkyl or joined together they form a cyclopropyl ring; R is independently selected from the group consisting of halogens and trifluoromethyl and p is 1, 2 or 3; A is C or N; E is a group of formula (B) or (C), wherein B is C(O)OH, C(O)O(C1-C3)alkyl, and C is selected from the group consisting of formula (I) m is 1,2 or 3, n is 0 or 1, W is -O-, -O(C1-C3 alkyl)-; -(C1-C3 alkyl)O-; -C(O)-; -C(=N-O(C1-C3 alkyl))-; -NH- or -NH(C1-C3alkyl)-; Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, -NH(C1-C3alkyl)-; -N(C1-C3alkyl)(C1-C3alkyl)-, a from 5 to 7 membered heterocyclic ring containing one nitrogen atom which is convalently bonded to Ar and optionally containing one or two heteroatoms selected from N, O and S; and a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from S, O e N, such heteroaromatic ring being substituted with one or two substituents selected from the group consisting of (C1-C3)alkyl, (C3-C5)cycloalkyloxy, (C1-C3)alkylcarbonyl. The compounds of the invention could be used for manufacturing a medicament for the treatment of pathologies which require the use of an antagonist of the EP4 receptor, such as the treatment of acute and chronic pain, inflammatory pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid artrhritis, cancer, endometriosis and migraine.
- -
-
Page/Page column 35
(2012/06/30)
-
- A novel series of potent and selective EP4 receptor ligands: Facile modulation of agonism and antagonism
-
A novel series of EP4 ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic
- Boyd, Michael J.,Berthelette, Carl,Chiasson, Jean-Franois,Clark, Patsy,Colucci, John,Denis, Danielle,Han, Yongxin,Lévesque, Jean-Francois,Mathieu, Marie-Claude,Stocco, Rino,Therien, Alex,Rowland, Steve,Wrona, Mark,Xu, Daigen
-
scheme or table
p. 484 - 487
(2011/02/27)
-
- Pyrrolopyrimidines and Pyrrolopyridines
-
Compounds of formula I in free or salt or solvate form, wherein X, T1, T3 and T4 have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
- -
-
Page/Page column 54-55
(2009/07/25)
-
- TROPANE COMPOUNDS
-
A compound according to Formula I or II: (I) or (II) wherein R1, R1b, R2, L1, and L2 and L2b are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
Page/Page column 366
(2009/05/30)
-