Efficient synthesis of trisubstituted pyrazoles and isoxazoles using a traceless "catch and release" solid-phase strategy.

An efficient three-component, two-step "catch and release" solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and isoxazoles has been developed. The first step involves a base-promoted condensation of a 2-sulfonyl- or a 2-carbonyl-acetonitrile derivative (1 or 7) with an isothiocyanate 2 and in situ immobilization of the resulting thiolate anion on Merrifield resin. Reaction of the resin-bound sulfonyl intermediate 4 with hydrazine or hydroxylamine, followed by release from the resin and intramolecular cyclization, affords 3,5-diamino-4-(arylsulfonyl)-1H-pyrazoles 5 or isoxazoles 6, respectively. Reaction of the resin-bound carbonyl intermediate 9 with hydrazine, on the other hand, leads to 3-(arylamino)-5-aryl-1H-pyrazole-4-carbonitriles 10.

Small molecule activators of the insulin receptor: potential new therapeutic agents for the treatment of diabetes mellitus.

Diabetes mellitus refers to a spectrum of syndromes characterized by abnormally high levels of glucose in blood. These syndromes are associated with an absolute (Type 1 diabetes) or relative (Type 2 diabetes) deficiency of insulin, coupled with varying degrees of peripheral resistance to the actions of insulin. Clinical studies have shown that controlling hyperglycemia significantly reduces the appearance and progression of the vascular complications associated with diabetes. Insulin's regulation of glucose homeostasis is mediated by a cascade of signaling events that take place upon insulin binding to its cell surface receptor. Autophosphorylation of the receptor and activation of its intrinsic tyrosine kinase are critical processes for transmitting these intracellular signals. Type 1 diabetes patients depend on exogenous insulin to achieve these effects, whereas Type 2 diabetes patients can accomplish a similar response through oral medications that increase the production of endogenous insulin or enhance its actions on the target tissues. Current biochemical and clinical evidence suggests that defects within the insulin receptor itself may be a cause of insulin resistance leading to Type 2 diabetes. This review focuses on the insulin receptor as a target for therapeutic intervention, and describes the recent discovery of small molecules that act on the receptor and either enhance or directly emulate the actions of insulin both in vitro and in vivo.

Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.

Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function.

Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.

Antitumor efficacy and molecular mechanism of TLK58747, a novel DNA-alkylating prodrug.

BACKGROUND: DNA-damaging agents are widely used for the treatment of human malignancies. Agents containing the multifunctional alkylating moiety tetrakis(2-chloroethyl)phosphorodiamidic acid are currently under development as cancer therapeutics. MATERIALS AND METHODS: TLK58747, a phophorodiamidate-based prodrug, was tested in vivo for antitumor efficacy and safety. The in vitro responses of tumor cells to TLK58747 were examined by cytotoxicity assays, cell cycle analysis, immunoblots and microscopy. RESULTS: TLK58747 was efficacious in xenograft models of human breast, pancreas, and prostate cancer, as well as in leukemia and glioma. It caused less bone marrow suppression in rats than did cyclophosphamide. In vitro, TLK58747 inhibited the growth of a wide variety of cancer cells and activated the DNA damage-response pathway, leading to G(2)/M cell cycle arrest and subsequent premature senescence or apoptosis. CONCLUSION: TLK58747 is a promising new alkylating agent with broad antitumor activity and superior safety that warrants further development.