- GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer
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Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
- Liang, Jun,Zbieg, Jason R.,Blake, Robert A.,Chang, Jae H.,Daly, Stephen,Dipasquale, Antonio G.,Friedman, Lori S.,Gelzleichter, Thomas,Gill, Matthew,Giltnane, Jennifer M.,Goodacre, Simon,Guan, Jane,Hartman, Steven J.,Ingalla, Ellen Rei,Kategaya, Lorn,Kiefer, James R.,Kleinheinz, Tracy,Labadie, Sharada S.,Lai, Tommy,Li, Jun,Liao, Jiangpeng,Liu, Zhiguo,Mody, Vidhi,McLean, Neville,Metcalfe, Ciara,Nannini, Michelle A.,Oeh, Jason,O'Rourke, Martin G.,Ortwine, Daniel F.,Ran, Yingqing,Ray, Nicholas C.,Roussel, Fabien,Sambrone, Amy,Sampath, Deepak,Schutt, Leah K.,Vinogradova, Maia,Wai, John,Wang, Tao,Wertz, Ingrid E.,White, Jonathan R.,Yeap, Siew Kuen,Young, Amy,Zhang, Birong,Zheng, Xiaoping,Zhou, Wei,Zhong, Yu,Wang, Xiaojing
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- SSAO INHIBITORS AND USE THEREOF
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Provided are a compound of formula (I') or (I), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of SSAO, a pharmaceutical composition comprising a compound of formula (I') or (I), and a method of treating or preventing a disease in which SSAO plays a role.
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Paragraph 00408
(2021/05/07)
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- POLY(PHOSPHOESTERS) FOR DELIVERY OF NUCLEIC ACIDS
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Disclosed are polymers comprising the moiety A, which is a moiety of formula I: and pharmaceutically acceptable salts thereof, wherein R, R1, R2, L, n1 and n2 are as defined herein. These polymers are useful for delivering nucleic acids to subject. These polymers and pharmaceutically acceptable compositions comprising such polymers and nucleic acids can be useful for treating various diseases, disorders and conditions.
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Paragraph 0401; 0404
(2020/09/15)
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- CRYSTAL OF CYCLIC PHOSPHONIC ACID SODIUM SALT AND METHOD FOR MANUFACTURING SAME
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An object of the present invention is to provide a crystal of a cyclic phosphonic acid sodium salt (2ccPA) with high purity and excellent storage stability and a method for producing the crystal. The present invention provides a crystal of a cyclic phosphonic acid sodium salt (2ccPA) represented by formula (1):
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Paragraph 0302; 0303; 0304; 0305; 0532; 0533
(2017/09/02)
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- ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH
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Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.
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Page/Page column 196
(2017/12/01)
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- 4,6-SUBSTITUTED-PYRAZOLO[1,5-a]PYRAZINES AS JANUS KINASE INHIBITORS
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Compounds of Formula I: and stereoisomers and pharmaceutically acceptable salts and solvates thereof in which R1, R2, R3 and R4 have the meanings given in the specification, are inhibitors of one or more JAK kinases and are useful in the treatment of JAK kinase-associated diseases and disorders, such as autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.
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Paragraph 00385
(2016/06/28)
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- BICYCLIC HETEROARYL UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS
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Compounds of Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring A, Ring C and X are as defined herein, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.
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Paragraph 00652
(2014/06/11)
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- Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics
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Several acyclic hydroxy-methylthio-amines with 3-5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and Escherichia coli and Neisseria meningitidis MTANs and gave Ki values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4- methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon-carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts.
- Clinch, Keith,Evans, Gary B.,Froehlich, Richard F.G.,Gulab, Shivali A.,Gutierrez, Jemy A.,Mason, Jennifer M.,Schramm, Vern L.,Tyler, Peter C.,Woolhouse, Anthony D.
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supporting information
p. 5181 - 5187
(2012/11/07)
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- Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands
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We designed and synthesized nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain. The ligand YR335 exhibited potent transcriptional activity, which was comparable to those of 1α,25-dihydroxyvitamin D3 and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above.
- Demizu, Yosuke,Takahashi, Takeo,Kaneko, Fumiya,Sato, Yukiko,Okuda, Haruhiro,Ochiai, Eiji,Horie, Kyohei,Takagi, Ken-Ichiro,Kakuda, Shinji,Takimoto-Kamimura, Midori,Kurihara, Masaaki
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scheme or table
p. 6104 - 6107
(2011/11/06)
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- BENZOXAZOLE DERIVATIVES
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It is intended to provide a benzoxazole derivative or a pharmaceutically acceptable salt or solvate thereof which is useful in the early diagnosis of a conformation disease; a composition or a kit containing the same for diagnosing a conformation disease; a medical composition for ttreating and/or preventing a conformation disease; and so on.
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Page/Page column 51-52
(2009/10/01)
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- BORON-CONTAINING SMALL MOLECULES
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This invention provides, among other things, novel compounds useful for treating bacterial infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.
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Page/Page column 210-211
(2009/01/23)
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- DEVELOPMENT OF MOLECULAR IMAGING PROBES FOR CARBONIC ANHYDRASE-IX USING CLICK CHEMISTRY
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The present application discloses methods for identifying inhibitors with high binding-affinity for the carbonic anhydrase-IX (CA-IX) enzyme using click chemistry and uses the candidates thereof as positron emission tomography (PET) imaging agents.
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Page/Page column 84-85
(2008/12/04)
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- Acyclic analogues of adenosine bisphosphates as P2Y receptor antagonists: Phosphate substitution leads to multiple pathways of inhibition of platelet aggregation
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Activation by ADP of both P2Y1 and P2Y12 receptors in platelets contributes to platelet aggregation, and antagonists at these receptor subtypes have antithrombotic properties. In an earlier publication, we have characterized the SAR as P2Y1 receptor antagonists of acyclic analogues of adenine nucleotides, containing two phosphate groups on a symmetrically branched aliphatic chain, attached at the 9-position of adenine. In this study, we have focused on antiaggregatory effects of P2Y antagonists related to a 2-chloro-N6-methyladenine-9-(2-methylpropyl) scaffold, containing uncharged substitutions of the phosphate groups. For the known nucleotide (cyclic and acyclic) bisphosphate antagonists of P2Y1 receptors, there was a significant correlation between inhibition of aggregation induced by 3.3 μM ADP in rat platelets and inhibition of P2Y1 receptor-induced phospholipase C (PLC) activity previously determined in turkey erythrocytes. Substitution of the phosphate groups with nonhydrolyzable phosphonate groups preserved platelet antiaggregatory activity. Substitution of one of the phosphate groups with O-acyl greatly reduced the inhibitory potency, which tended to increase upon replacement of both phosphate moieties of the acyclic derivatives with uncharged (e.g., ester) groups. In the series of nonsymmetrically substituted monophosphates, the optimal antagonist potency occurred with the phenylcarbamate group. Among symmetrical diester derivatives, the optimal antagonist potency occurred with the di(phenylacetyl) group. A dipivaloyl derivative, a representative uncharged diester, inhibited ADP-induced aggregation in both rat (KI 3.6 μM) and human platelets. It antagonized the ADP-induced inhibition of the cyclic AMP pathway in rat platelets (IC50 7 μM) but did not affect hP2Y1 receptor-induced PLC activity measured in transfected astrocytoma cells. We propose that the uncharged derivatives are acting as antagonists of a parallel pro-aggregatory receptor present on platelets, that is, the P2Y12 receptor. Thus, different substitution of the same nucleoside scaffold can target either of two P2Y receptors in platelets.
- Xu, Bin,Stephens, Andrew,Kirschenheuter, Gary,Greslin, Arthur F.,Cheng, Xiaoquin,Sennelo, Joe,Cattaneo, Marco,Zighetti, Maddalena L.,Chen, Aishe,Kim, Soon-Ai,Kim, Hak Sung,Bischofberger, Norbert,Cook, Gary,Jacobson, Kenneth A.
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p. 5694 - 5709
(2007/10/03)
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- Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design
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A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, his tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein- ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.
- Melnick, Michael,Reich, Siegfried H.,Lewis, Kathy K.,Mitchell Jr., Lennert J.,Nguyen, Dzuy,Trippe, Anthony J.,Dawson, Heather,Davies II, Jay F.,Appelt, Krzysztof,Wu, Bor-Wen,Musick, Linda,Gehlhaar, Dan K.,Webber, Stephanie,Shetty, Bhasker,Kosa, Maha,Kahil, Deborah,Andrada, Dominic
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p. 2795 - 2811
(2007/10/03)
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- Novel acyclonucleotides: Synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine
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A series of phosphonoalkenyl and (phosphonoalkenyl)oxy derivatives of purines and a pyrimidine were synthesized. These compounds are the first reported acyclonucleotides which incorporate the α,β-unsaturated phosphonic acid moiety as the phosphate mimic and include compounds in which the acyclic substituent is attached to N-9 of a purine or N-1 of a pyrimidine by either a nitrogen-carbon or a nitrogen-oxygen bond. The phosphonoalkenyl-substituted compounds 7a-c, 8a-c, 9, 10, and 12 were prepared either by Mitsunobu coupling of alcohols with purine or pyrimidine derivatives or by alternative alkylations of the heterocyclic bases. The (phosphonoalkenyl)oxy derivatives 7d-g, 8d-g, and 11 were synthesized by coupling of alcohols with 9- hydroxypurines or a 1-hydroxypyrimidine under Mitsunobu conditions. The novel acyclonucleotides were tested for activity against herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), visna virus, and human immunodeficiency virus type 1 (HIV-1). Guanine derivatives were moderately to extremely cytotoxic, but the adenines were less toxic to cells. At the concentrations tested, (Z)-isomers in the unbranched series had no activity against herpes viruses or HIV-1. (E)-9- [(4-Phosphonobut-3-enyl)oxy]adenine (7d) displayed selective activity against HIV-1, (E)-2,6-diamino-9-(4-phosphonobut-3-enyl)purine (9) showed selective antiretrovirus activity, and (E)-9-[2-(hydroxymethyl)-4-phosphonobut-3- enyl]adenine (7c) showed selective antiherpesvirus (VZV and CMV) activity.
- Harnden,Parkin,Parratt,Perkins
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p. 1343 - 1355
(2007/10/02)
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- SYNTHESIS OF 5,5'-DIHYDROXYLEUCINE AND 4-FLUORO-5,5'-DIHYDROXYLEUCINE, THE REDUCTION PRODUCTS OF 4-CARBOXYGLUTAMIC AND 4-CARBOXY-4-FLUOROGLUTAMIC ACIDS
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Schemes for the synthesis of 5,5'-dihydroxyleucine 3 and its 4-fluoro analog 7 involving the condensation of a suitable 'aminoacid moiety' with 2,2-dimethyl-5-iodomethyl-1,3-dioxane 15D or its fluoro analog 27A were tested.The anion of the ethyl N-diphenylmethylene-glycinate 25 gave better yields of 3 than the classical anion of diethyl acetamidomalonate.This strategy could not be successfully applied to the synthesis of 7, which could be prepared by reduction of a suitably protected 4-fluoro-4-carboxyglutamate with BMS.
- Dubois, Joelle,Foures, Christine,Bory, Sonia,Falcou, Serge,Gaudry, Michel,Marquet, Andree
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p. 1001 - 1012
(2007/10/02)
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