cas 571189-78-1, 5-morpholinopyridin-2-amine

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Mild, General, and Regioselective Synthesis of 2-Aminopyridines from Pyridine N -Oxides via N -(2-Pyridyl)pyridinium Salts
A synthesis of 2-aminopyridines from pyridine N-oxides via their corresponding N-(2-pyridyl)pyridinium salts has been demonstrated and investigated. The reaction sequence features a highly regioselective conversion of the N-oxide into its pyridinium salt
Xiong, Hui,Hoye, Adam T.
supporting information
p. 371 - 375
(2022/01/27)

Discovery and in Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor
Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor"was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.
Chen, Xing,Yan, Yaoyao,Zhang, Zhaoyan,Zhang, Faming,Liu, Mingming,Du, Leran,Zhang, Haixia,Shen, Xiaobao,Zhao, Dahai,Shi, Jing Bo,Liu, Xinhua
p. 11857 - 11885
(2021/09/02)

ARYL AND HETEROARYL-CARBOXAMIDE SUBSTITUTED HETEROARYL COMPOUNDS AS TYK2 INHIBITORS
Novel carboxamide substituted compounds of Formula (I) are disclosed; as well as processes for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Tyrosine Kinase 2 (Tyk2).
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(2021/10/15)

DERIVATIVES OF 4-(IMIDAZO[L,2-A]PYRIDIN-3-YL)-N-(PYRIDINYL)PYRIMIDIN- 2-AMINE AS THERAPEUTIC AGENTS
A novel class of heteroaryl compounds for use in the prevention and/or treatment of proliferative diseases and conditions including cancers. The compounds are considered to be capable of inhibiting cell proliferation by inhibiting the activity of FLT3 and its mutant forms and/or other protein kinases such as CDKs. The compounds have the general structure I:
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Paragraph 0083; 0089; 00137; 00142

(2021/01/29)

HPK1 ANTAGONISTS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.
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Paragraph 0452; 0454; 0457; 0458

(2021/03/19)

Discovery and SARs of 5-Chloro- N4-phenyl- N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity
Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.
Wang, Yang,Chen, Xing,Yan, Yaoyao,Zhu, Xiaochen,Liu, Mingming,Liu, Xinhua
p. 3327 - 3347
(2020/04/08)

Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents
A total of 26 compounds based on osthole skeleton were designed, synthesized. Their cytoprotective abilities of antioxidation, anti-inflammation and Aβ42(Amyloid β-protein 42)-induced neurotoxicity were evaluated by MTT assays. Mechanism of the action of selected compounds were investigated by molecular docking. AlogP, logS and blood–brain barrier (BBB) permeability of all these compounds were simulated by admetSAR. Most of the compounds showed better antioxidative and anti-inflammatory activities compared with osthole, especially OST7 and OST17. The compound OST7 showed relative high activity in neuroprotection against H2O2 (45.7 ± 5.5%), oxygen glucose deprivation (64.6 ± 4.8%) and Aβ42 (61.4 ± 5.2%) at a low concentration of 10 μM. EC50 of selected compounds were measured in both H2O2 and OGD induced cytotoxicity models. Moreover, NO inhibiting ability of OST17(50.4 ± 7.1%) already surpassed the positive drug indomethacin. The structure activity relationship study indicated that introduction of piperazine group, tetrahydropyrrole group and aromatic amine group might be beneficial for enhancement of osthole neuroprotective properties. Molecular docking explained that the reason OST7 exhibited relatively stronger neuroprotection against Aβ because of the greater area of interactions between molecule and target protein. OST7 and OST17 both provided novel methods to investigate osthole as anti-AD drugs.
Zhang, Li,Wu, Yuhang,Yang, Guixiang,Gan, Haixian,Sang, Dayong,Zhou, Jiye,Su, Lin,Wang, Rui,Ma, Lei
(2020/11/03)

TYK2 INHIBITORS AND USES THEREOF
Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
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Paragraph 00550

(2020/06/10)

UREA DERIVATIVES AS INHIBITORS OF ASK1
The present technology is directed to compounds, compositions, and methods related to inhibition of ASK1. In particular, the present compounds (e.g., compounds of Formula I as defined herein) and compositions may be used to treat ASK1-mediated disorders and conditions, including, e.g., fibrotic diseases and acute and chronic liver diseases, among others.
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(2019/06/05)

Streamlined Synthesis of Diaminopyridines by Pd-Catalyzed Ammonia Coupling with Deactivated Amino-Chloropyridines
An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes include cost and wider availability of the bromo-chloropyridine starting materials and the straightforward accessibility to an extended array of diaminopyridine regioisomers. The key enabler of this synthetic strategy is the development of an unprecedented palladium-catalyzed coupling reaction of ammonia with chloropyridines deactivated by the presence of an alkylamino substituent. The coupling reaction was accomplished with very low catalyst loadings under remarkably mild reaction conditions, making the system particularly suitable for both academic and industrial applications. The utility of this methodology is exemplified by the application to the synthesis of highly relevant scaffolds, including the synthetic intermediates of the marketed drugs Ribociclib and Palbociclib.
Bourriquen, Florian,Bruneau-Voisine, Antoine,Jeandin, Aliénor,Stihle, Etienne,Fantasia, Serena
supporting information
p. 9006 - 9011
(2019/06/24)

Antimalarial Lead-Optimization Studies on a 2,6-Imidazopyridine Series within a Constrained Chemical Space to Circumvent Atypical Dose-Response Curves against Multidrug Resistant Parasite Strains
A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
Le Manach, Claire,Paquet, Tanya,Wicht, Kathryn,Nchinda, Aloysius T.,Brunschwig, Christel,Njoroge, Mathew,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Wittlin, Sergio,Eyermann, Charles J.,Basarab, Gregory S.,Duffy, James,Fish, Paul V.,Street, Leslie J.,Chibale, Kelly
p. 9371 - 9385
(2018/10/24)

Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents
Background and Purpose: Cyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6. Experimental Approach: The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling. Key Results: We discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate. Conclusions and Implications: We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy.
Tadesse, Solomon,Bantie, Laychiluh,Tomusange, Khamis,Yu, Mingfeng,Islam, Saiful,Bykovska, Nataliya,Noll, Benjamin,Zhu, Ge,Li, Peng,Lam, Frankie,Kumarasiri, Malika,Milne, Robert,Wang, Shudong
p. 2399 - 2413
(2018/05/14)

Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors
CDK4/6 pathway is an attractive target for development of anti-cancer drugs. Herein, we reported the design and synthesis of a series of 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives as selective CDK4/6 inhibitors. Applied with the optimizing strategy to the initial scaffold, it is found that compound 13n is able to selectively inhibit CDK4 and CDK6 with IC50 values 0.01 and 0.026 μM, respectively. The compound showed good anti-proliferative activity when tested in a panel of tumor cell lines with CDK4/6 related mechanism of action, the results clearly suggest that compound 13n works much better than Ly2385219 which is a selective CDK4/6 inhibitor. This compound was also found to have favorable pharmacokinetic parameters. Taken together, compound 13n could be selected for further preclinical evaluation.
Zhao, Hui,Hu, Xiaoxia,Cao, Kai,Zhang, Yue,Zhao, Kuantao,Tang, Chunlei,Feng, Bainian
p. 935 - 945
(2018/09/04)

ANTIPROLIFERATIVE PYRIMIDINE-BASED COMPOUNDS
This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
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Page/Page column 147; 148; 153

(2018/02/28)

PYRIMIDINE-BASED ANTIPROLIFERATIVE AGENTS
This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
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Page/Page column 161; 162; 166; 167

(2018/02/28)

PYRIMIDINE-BASED COMPOUNDS FOR THE TREATMENT OF CANCER
This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
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Page/Page column 105; 110

(2018/02/28)

Pyrimidine and pyrimidine dione CDK4/6 kinase inhibitors and uses thereof
The invention belongs to the field of chemical medicine, relates to pyrimidine and pyrimidine dione CDK4/6 kinase inhibitor and its application, the pyrimidine and pyrimidine dione CDK4/6 kinase inhibitors of formula I shown in the compound or its pharmaceutically acceptable salt, and pharmaceutical compositions containing these compounds and these compounds or compositions of the pharmaceutical preparation in the application, the present invention provides a pyrimidine and pyrimidine dione compounds to CDK4 and CDK6 kinase has better inhibition activity, to breast cancer cell has significant inhibition function, can effectively reduce the incidence of tumor, extension of the tumor to the lives of patients,
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Paragraph 0075; 0076; 0077; 0078

(2018/07/30)

Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation
Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
Tadesse, Solomon,Yu, Mingfeng,Mekonnen, Laychiluh B.,Lam, Frankie,Islam, Saiful,Tomusange, Khamis,Rahaman, Muhammed H.,Noll, Benjamin,Basnet, Sunita K. C.,Teo, Theodosia,Albrecht, Hugo,Milne, Robert,Wang, Shudong
p. 1892 - 1915
(2017/03/17)

NOVEL CLOSTRIDIUM DIFFICILE TOXIN INHIBITORS
The present invention relates to benzodiazepine derivative compounds of formula (I), or pharmaceutically acceptable salts thereof. The present benzodiazepine compounds are useful Clostridium difficile inhibitors in the treatment of Clostridium difficile infection in humans. The present invention provides a pharmaceutical composition containing benzodiazepine compounds of formula (I) and a method of making as well as a method of using the same in treating patients infected with Clostridium difficile infection by administering the same. The compounds of the present invention may be used in combination with additional antibiotics or anti-toxin antibody drugs.
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(2018/01/17)

Copper-catalyzed selective C-N bond formation with 2-amino, 2-hydroxy and 2-bromo-5-halopyridine
A copper-catalyzed 1,2-diol amination at the electron-rich C-5 position of unprotected 2-amino/2-hydroxy-5-halopyridine provided excellent yields. Selective amination preferably at C-5 in 2-bromo-5-iodopyridine was achieved under the same conditions. The selective, generally mild and economical coupling reaction at C-5 position described herein could be achieved with amines, heterocycles and amides.
Roy, Swarnali,Paul, Barnali,Mukherjee, Ayan,Kundu, Biswajit,Talukdar, Arindam
p. 44366 - 44370
(2017/09/26)

COMBINATIONS AND DOSING REGIMES TO TREAT RB-POSITIVE TUMORS
This invention directed to methods for treating select RB-positive cancers and other Rb- positive abnormal cellular proliferative disorders using CDK4/6 inhibitors in specific dosing and combination or alternation regimes. In one aspect, treatments of select RB-positive cancers are disclosed using specific CDK4/6 inhibitors in combination or alternation with another chemotherapeutic, for example, an additional kinase inhibitor, PD-1 inhibitor, or BCL-2 inhibitor, or combination thereof.
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Page/Page column 103; 117

(2016/06/01)

TREATMENT OF RB-NEGATIVE TUMORS USING TOPOISOMERASE INHIBITORS IN COMBINATION WITH CYCLIN DEPENDENT KINASE 4/6 INHIBITORS
This invention is in the area of improved therapeutic combinations for and methods of treating selected retinoblastoma (Rb)-negative cancers and Rb-negative abnormal cellular proliferative disorders using particular topoisomerase inhibitors and specific c
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Page/Page column 98; 112

(2016/06/01)

COMPOUNDS FOR REGULATING FAK AND/OR SRC PATHWAYS
The present application provides novel optionally substituted fused pyridine and pyrimidine bicyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating FAK and/or Src activity by administering a therapeutically effective amount of one or more of the compounds to a subject. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the FAK and/or Src pathway. Advantageously, these compounds perform as dual FAK and/or Src inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.
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(2015/03/28)

TYK2 INHIBITORS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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(2015/09/28)

IMIDAZOPYRIDINES SYK INHIBITORS
Certain imidazopyridines (I) and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.
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(2014/06/11)

BENZONITRILE DERIVATIVES AS KINASE INHIBITORS
Compounds of the formula I, in which R1, R2, X and Y have the meanings indicated in Claim 1, are inhibitors of TBK1 and IKKε and can be employed, inter alia, for the treatment of cancer and inflammatory diseases.
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Paragraph 0569-0570

(2014/08/19)

3-(ARYL- OR HETEROARYL-AMINO)-7-(3,5-DIMETHOXYPHENYL)ISOQUINOLINE DERIVATIVES AS FGFR INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISORDERS OR DYSPLASIA
The invention relates to compounds of formula (I) wherein R1, R2, R2a, R3 have the meaning as cited in the description and the claims. Said compounds are useful as FGFR inhibitors. The invention also relates to
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Page/Page column 25; 28

(2014/04/04)

TRANSIENT PROTECTION OF NORMAL CELLS DURING CHEMOTHERAPY
This invention is in the area of improved compounds, compositions and methods of transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, improved protection of healthy cells is disclosed using disclosed compounds that act as highly selective and short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.
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Page/Page column 110; 124; 125

(2014/09/29)

SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
Provided herein are novel substituted bicyclic aza-heterocycle sirtuin- modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin- modulating compound in combination with another therapeutic agent.
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(2013/05/09)

CDK INHIBITORS
Compounds of formulae I, II or III, and pharmaceutically acceptable salts thereof, are useful as CDK inhibitors.
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Paragraph 0159-0160; 0223-0224

(2013/09/26)

IMIDAZOPYRIDINES SYK INHIBITORS
Certain imidazopyridines (I) and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.
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(2011/10/05)

PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE
Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 353; 354

(2011/11/30)

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: Selection of the scaffold
HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC50 of 3 nM against wild type HIV infected T-cells.
Jones, Eric D.,Vandegraaff, Nick,Le, Giang,Choi, Neil,Issa, William,MacFarlane, Katherine,Thienthong, Neeranat,Winfield, Lisa J.,Coates, Jonathan A.V.,Lu, Long,Li, Xinming,Feng, Xiao,Yu, Changjiang,Rhodes, David I.,Deadman, John J.
scheme or table
p. 5913 - 5917
(2010/11/18)

BICYCLIC PYRIMIDINONES AND USES THEREOF
The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compoundof Formula I is also provided.
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(2008/12/06)

IMIDAZOLOPYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
Novel imidazo[1,2-a]pyrazine compounds are disclosed that have a formula ( I ) represented by the following:The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, arthritis, inflammation, and others.
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Page/Page column 106

(2008/06/13)

Monodentate phosphines provide highly active catalysts for Pd-catalyzed C-N bond-forming reactions of heteroaromatic halides/amines and (H)N-heterocycles
(Chemical Equation Presented) A good alternative: Highly reactive catalysts based on palladium and dialkylbiarylphosphino ligands provide unprecedented reactivity and selectivity in C-N bond-forming processes. The bulky monophosphine catalyst system Pd/1 was effective for the reaction of aryl/heteroaryl halides bearing primary amides and 2-aminoheterocycles (see scheme; dba = dibenzylideneacetone, R = CONH2, NH2), thus showing that monodentate phosphines are viable alternatives to, and sometimes superior to, chelating ligands.
Anderson, Kevin W.,Tundel, Rachel E.,Ikawa, Takashi,Altman, Ryan A.,Buchwald, Stephen L.
p. 6523 - 6527
(2007/10/03)

Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6
A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G1 block at concentrations up to 100-fold the IC50 for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.
Toogood, Peter L.,Harvey, Patricia J.,Repine, Joseph T.,Sheehan, Derek J.,VanderWel, Scott N.,Zhou, Hairong,Keller, Paul R.,McNamara, Dennis J.,Sherry, Debra,Zhu, Tong,Brodfuehrer, Joanne,Choi, Chung,Barvian, Mark R.,Fry, David W.
p. 2388 - 2406
(2007/10/03)