Jefferson Wright Tilley

Pentadienyl carboxamide derivatives as antagonists of platelet activating factor

A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).

Glucokinase activators as new type 2 diabetes therapeutic agents

Background: Small molecule glucokinase activators (GKAs) represent a new strategy to treat type 2 diabetes. Glucokinase (GK) primarily exerts its effect through modulatory actions in the pancreatic β-cells and the liver. It couples insulin secretion in the pancreas with plasma glucose concentration, and improves glucose utilization in the liver, thus affecting two key aspects of glucose homeostasis. Objective and method: To review currently disclosed GKA structures and to classify them based on the key structural features. For this purpose, the data from patent disclosures and publications are used. Also, published in vitro findings on related lead GKAs are used to compare their effect on GK kinetics. Results and conclusion: The most common GKA pharmacophore consists of a center, which can be a carbon or an aromatic ring, and three attachments. Two of these are hydrophobic groups, with at least one of them being an aromatic ring. The third attachment, without exception, consists of an H-bond donor–acceptor pair in the form of a heterocyclic amine, or an N-acyl urea. These structurally diverse GKAs show important differences in their effects on the kinetic properties of GK.

NMR characterization of interleukin-2 in complexes with the IL-2Rα receptor component, and with low molecular weight compounds that inhibit the IL-2/IL-Rα interaction

Nuclear magnetic resonance (NMR) methods were employed to study the interaction of the cytokine Interleukin‐2 (IL‐2) with the α‐subunit of its receptor (IL‐2Rα), and to help understand the behavior of small molecule inhibitors of this interaction. Heteronuclear 1H‐15N HSQC experiments were used to identify the interaction surface of 15N‐enriched Interleukin‐2 (15N‐IL‐2) in complex with human IL‐2Rα. In these experiments, chemical shift and line width changes in the heteronuclear single‐quantum coherence (HSQC) spectra upon binding of 15N‐IL‐2 enabled classification of NH atoms as either near to, or far from, the IL‐2Rα interaction surface. These data were complemented by hydrogen/deuterium (H/D) exchange measurements, which illustrated enhanced protection of slowly‐exchanging IL‐2 NH protons near the site of interaction with IL‐2Rα. The interaction surface defined by NMR compared well with the IL‐2Rα binding site identified previously using mutagenesis of human and murine IL‐2. Two low molecular weight inhibitors of the IL‐2/IL‐2Rα interaction were studied: one (a cyclic peptide derivative) was found to mimic a part of the cytokine and bind to IL‐2Rα; the other (an acylphenylalanine derivative) was found to bind to IL‐2. For the interaction between IL‐2 and the acylphenylalanine, chemical shift perturbations of 15N and 15NH backbone resonances were tracked as a function of ligand concentration. The perturbation pattern observed for this complex revealed that the acylphenylalanine is a competitive inhibitor—it binds to the same site on IL‐2 that interacts with IL‐2Rα.

Novel glucokinase activators: a patent review (2008 – 2010)

Importance of the field: Small molecule glucokinase activators (GKAs) continue to represent a potential strategy to treat type 2 diabetes (T2D). Glucokinase (GK) primarily exerts its effect through modulatory actions in pancreatic β-cells and hepatocytes. It couples insulin secretion in the pancreas with plasma glucose concentration and improves glucose utilization in the liver, thus, affecting two key aspects of glucose homeostasis. There has been an intense interest in GKAs within the pharmaceutical industry ever since the first report of a low molecular mass activator in 2003. The key drivers for this interest are the robust glucose lowering activity observed with GKAs in preclinical T2D animal models and early reports of efficacy in T2D patients. Areas covered in this review: The objective is to review GKA structures disclosed during the 2008 – 2010 period and classify them based on key structural features. For this purpose, only compound data from patent disclosures were used. What the reader will gain: The reader would gain a detailed view of structural diversity of the GKA field disclosed during the review period. Take home message: There continues to be a high level of interest within the pharmaceutical industry in novel GKAs. Several new and highly potent structure types were reported for the first time in the past 3 years. Common features of all of them include a hydrogen bond donor–acceptor pair that makes contact with the backbone CO- and NH- bonds of Arg 63 residue on GK and two hydrophobic groups. During this review period, several GKAs progressed to Phase II clinical testing and the data on their safety and efficacy profiles are eagerly awaited.

N-Benzylpyroglutamyl-l-phenylalanine derivatives as VCAM/VLA-4 antagonists

A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.

Discovery of Orally Active Carboxylic Acid Derivatives of 2-Phenyl-5-trifluoromethyloxazole-4-carboxamide as Potent Diacylglycerol Acyltransferase-1 Inhibitors for the Potential Treatment of Obesity and Diabetes

Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

VLA-4 antagonists

Evidence has accumulated over recent years for an important role for VLA-4 in inflammatory disease. Work with antibodies directed against VLA-4 or its primarily ligand VCAM-1 and peptides that mimic the Leu-Asp-Val (LDV) VLA-4 binding epitope on fibronectin suggest that asthma, rheumatoid arthritis, multiple sclerosis, atherosclerosis and inflammatory bowel disease are amenable to treatment with a VLA-4 antagonist. Several types of molecules, including humanised monoclonal antibodies, VCAM antisense polynucleotides, peptide mimetics of the LDV sequence and 4-substituted N-acylphenylalanine derivatives, constitute the major compound classes currently under development. Clinical trials with several compounds are underway with early reports of efficacy with the monoclonal antibody natalizumab in multiple sclerosis and Crohn’s disease.

Recent Advances in Therapeutic Approaches to Type 2 Diabetes

Publisher Summary This chapter presents the recent advances in therapeutic approaches to type 2 diabetes (T2D). The developments discussed in this chapter, can be broadly classified into (1) enhancers of insulin release, (2) enhancers of insulin action, (3) inhibitors of hepatic glucose production, and (4) inhibitors of glucose absorption from the gut. Major current therapies for T2D include sulfonylureas, metformin, and TZDs. Each of these therapies has limitations with regard to their efficacy or side-effect profile. Among the targets discussed in this chapter, the most advanced are those based on glucagon-like peptide 1 (GLP-1) agonist activity—that is, Exenatide, and DPPIV (dipeptidyl peptidase IV )inhibitors. Both strategies are directed to potentiate the actions of GLP-1 on insulin secretion and have shown promise in Phase II/III clinical trials. These agents may avoid complications related to hypoglycemia and also may limit the potential for weight gain, thus complementing existing therapies. The discovery of potent Protein tyrosine phosphatase 1B (PTP1B) inhibitors remains a challenge; however, progress is being made and effective PTP1B inhibitors are expected to show beneficial effects in reducing insulin resistance and modulating weight gain. Glucokinase activation is the newest strategy disclosed.

N-Acyl-l-phenylalanine derivatives as potent VLA-4 antagonists that mimic a cyclic peptide conformation

A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.

The design and synthesis of potent cyclic peptide VCAM–VLA-4 antagonists incorporating an achiral Asp-Pro mimetic

The Asp-Pro sequence of the cyclic peptide Ac-HN-Tyr-Cys*-Asp-Pro-Cys*-OH (1) could be replaced with the achiral dipeptide mimetic 1-(2-aminoethyl)cyclpentylcarboxylic acid with retention of potent inhibition of the VCAM-VLA-4 interaction.