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1.
J Med Chem ; 54(12): 4092-108, 2011 Jun 23.
Article in English | MEDLINE | ID: mdl-21608528

ABSTRACT

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzocycloheptenes/chemical synthesis , Pyridines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzocycloheptenes/pharmacokinetics , Benzocycloheptenes/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Drug Screening Assays, Antitumor , Female , Haplorhini , Humans , Mice , Mice, Nude , Models, Molecular , Mutation , Neoplasm Transplantation , Phosphorylation , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Receptor Protein-Tyrosine Kinases/genetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Transplantation, Heterologous
2.
J Am Chem Soc ; 127(43): 15026-7, 2005 Nov 02.
Article in English | MEDLINE | ID: mdl-16248632

ABSTRACT

Enantioselective total synthesis of reblastatin is described. The synthesis highlights hydrozirconation, transmetalation, aldehyde addition sequence to install E-trisubstituted olefin and C7 stereocenter, and the first use of an intramolecular Buchwald-like amidation reaction to close the 19-membered macrolactam.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Quinones/chemical synthesis , Anti-Bacterial Agents/pharmacology , Indicators and Reagents , Models, Chemical
3.
J Am Chem Soc ; 126(35): 10913-22, 2004 Sep 08.
Article in English | MEDLINE | ID: mdl-15339176

ABSTRACT

We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.


Subject(s)
Epothilones/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Epothilones/chemistry , Epothilones/pharmacology , Humans , Mice , Mycobacterium/chemistry , Xenograft Model Antitumor Assays
4.
J Nat Prod ; 67(2): 139-43, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14987048

ABSTRACT

There is wide interest in the epothilones, which like the taxoids initiate cytotoxicity through microtubule stabilization. Briefly described is an application of a ring-closing metathesis reaction toward the synthesis of epothilones as carried out in our laboratory. This has led to the discovery of the (E)-9,10-dehydroepothilones as second-generation anticancer drug candidates.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Epothilones/chemistry , Epothilones/chemical synthesis , Drug Screening Assays, Antitumor , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Taxoids
7.
J Am Chem Soc ; 125(10): 2899-901, 2003 Mar 12.
Article in English | MEDLINE | ID: mdl-12617656

ABSTRACT

The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Epothilones/chemical synthesis , Epothilones/pharmacology , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Cell Division/drug effects , Drug Design , Drug Screening Assays, Antitumor , Drug Stability , Epothilones/blood , Epothilones/chemistry , HCT116 Cells , Humans , Structure-Activity Relationship
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