John R. Porter

Small molecule c-Met kinase inhibitors: a review of recent patents

Importance of the field: c-Met kinase is the receptor for hepatocyte growth factor. Primarily expressed on epithelial and mesenchymal cells its normal function is associated with wound healing, liver regeneration and embryo development. However, dysregulation of c-Met through overexpression, gene amplification, mutation or a ligand-dependent autocrine/paracrine loop is associated with tumorigenesis. c-Met dysregulation in human cancer patients is typically associated with a poor prognosis, aggressive disease, increased metastasis and shortened patient survival. Targeting the hepatocyte growth factor/c-Met signalling pathway as a means of cancer therapy has, therefore, become increasingly popular with a number of different therapeutic approaches undergoing clinical trials. Areas covered by this review: This review covers the patent applications for small molecule c-Met kinase inhibitors since 2007, attempts to place them in context from a structural point of view and examines their potential applications in cancer therapy. What the reader will gain: Readers will gain an overview of the structural types of c-Met inhibitors, the major players in the field and an insight into what is progressing into the clinic. Take home message: This area is developing rapidly and the results of the various ongoing clinical trials will generate an increased understanding of the potential benefits and pitfalls of c-Met inhibitors as therapeutic agents.

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.

Potent and selective inhibitors of gelatinase-a 1. hydroxamic acid derivatives

Abstract A series of hydroxamic acid derivatives were prepared. By introducing aromatic substituents at the P1′ and P3′ positions highly potent gelatinase-A inhibitors, which possess a high degree of selectivity over collagenase and stromelysin, were obtained. These inhibitors may be of therapeutic value in the control of tumour metastasis.

CDP840. A prototype of a novel class of orally active anti-Inflammatory phosphodiesterase 4 inhibitors

The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC(50) 4nM). CDP840 is non-emetic in the ferret at 30mgkg(-1) (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig.

Potent and selective inhibitors of gelatinase-A 2. carboxylic and phosphonic acid derivatives

Abstract A series of zinc binding groups was introduced into a pseudopeptide sequence containing aromatic groups in the P1′ position in order to obtain selective inhibitors of gelatinase-A. Carboxylic acid and phosphonic acid groups provided the most potent inhibitors

Squaric acid derivatives as VLA-4 integrin antagonists.

SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.

Review Oncologic, Endocrine & Metabolic: Recent developments in matrix metalloproteinase inhibitors

The matrix metalloproteinases (MMPs) are a family of endopeptidases that are involved in the degradation and remodelling of the extracellular matrix of connective tissues and basement membranes. There is increasing evidence that these molecules are involved in a variety of degradative diseases such as arthritis and cancer. This review summarises recent developments in the design and application of small molecule MMP inhibitors disclosed in the recent patent and primary literature.

Dehydrophenylalanine derivatives as VLA-4 integrin antagonists

We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.

Discovery and evaluation of potent, cysteine-based α4β1 integrin antagonists

Abstract Acyclic, disulphide derivatives of cysteine have been identified as moderately potent antagonists of α4β1-mediated leukocyte cell adhesion to VCAM. This communication describes how they were discovered from a simple l -cystine derivative and using the structure–activity data of C*DThioPC* related cyclic peptides.