Celia Dominguez

Design, synthesis, and biological evaluation of potent c-Met inhibitors.

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

Discovery of a Potent, Selective, and Orally Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)

Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.

Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.

Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.

The de novo design and synthesis of cyclic urea inhibitors of factor Xa: Initial sar studies

In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.

Biaryl substituted alkylboronate esters as thrombin inhibitors

Abstract Thrombin is a serine protease that plays an important role in the blood coagulation cascade, and is a target enzyme for new therapeutic agents. Ac-(D)-Phe-Pro-boroArg-OH (DuP 714) was found to be a highly effective thrombin inhibitor. In order to reduce the peptidic nature of DuP 714, we have designed a series of novel biaryl substituted alkylboronate esters as potent thrombin inhibitors. The most potent compounds have subnanomolar affinity for thrombin.

The role of novel ligands in the biological characterization of sigma receptors

Publisher Summary This chapter discusses the role of novel ligands in the biological characterization of sigma receptors. Investigation of the physiological and pharmacological role of sigma receptors is a relatively new area that has been facilitated by the development of high affinity and selective sigma receptor ligands including putative agonists and antagonists. Many different classes of drugs, ranging from steroids such as progesterone to neuroleptics such as haloperidol, exhibit high affinity for sigma receptors. This binding activity of the neuroleptic drugs suggested that sigma receptors may be responsible, at least in part, for the motor side-effects of these drugs. Sigma receptor research has been greatly facilitated by the development of chemical tools ranging from antagonists that allow the probing of sigma receptor function to PET scanning ligands, which have allowed visualization of sigma receptors in mammalian brain.

Synthesis of isothiocyanato-1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidines, potential irreversible ligands at the dopamine re-uptake site

Isomeric isothiocyanate derivatives 2–7 of the potent dopamine re-uptake (DA) inhibitor 1-[1-(2-benzo-[b]thienyl)cyclohexyl]piperidine (BTCP 1) have been synthesized as potential irreversible ligands for this site. NaNO2–CF3CO2H provided a mild procedure for mononitration of the benzo[b]thienyl ring of 1 as a route to aryl isothiocyanates 5–7. Novel methodology, utilizing 3,3-ethylenedioxypentane-1,5-diol dimethanesulfonate ester is described for the synthesis of piperidone 13, a precursor for 4-isothiocyanatopiperidine 2. NaBH4 or LiAlH4 reduction of 4-(2-benzo[b]thienyl)-4-hydroxycyclohexanone 18 and 4-(2-benzo[b]thienyl)-4-(piperidino)cyclohexanone oxime 35 gives the corresponding cis-diol 21 and cis-cyclohexane-1,4-diamine 36 as the major isomers which have been investigated as precursors to the cyclohexane ring isothiocyanates 3 and 4. Alternative routes to 3 and 4 are compared and their stereochemical outcome investigated.