Investigation of Potential Bioisosteric Replacements for the Carboxyl Groups of Peptidomimetic Inhibitors of Protein Tyrosine Phosphatase 1B:  Identification of a Tetrazole-Containing Inhibitor with Cellular Activity

Abstract

Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that, together with protein tyrosine kinases, control the level of intracellular tyrosine phosphorylation, thus regulating many cellular functions. PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. We previously reported a series of small molecular weight peptidomimetics as competitive inhibitors of PTP1B, with the most active analogues having K(i) values in the low nanomolar range. Furthermore, we confirmed that the O-carboxymethyl salicylic acid moiety is a remarkably effective novel phosphotyrosine mimetic. Because of the low cell permeability of this compound class, it was important to investigate the possibility of replacing one or both of the remaining carboxyl groups while maintaining PTP1B inhibitory activity. The analogues described herein further support the importance of an acidic functionality at both positions of the tyrosine head moiety. An important discovery was the ortho tetrazole analogue 29 (K(i) = 2.0 microM), which was equipotent to the dicarboxylic acid analogue 2 (K(i) = 2.0 microM). Solution of the X-ray cocrystal structure of the ortho tetrazole analogue 29 bound to PTP1B revealed that the tetrazole moiety is well-accommodated in the active site and binds in a fashion similar to the ortho carboxylate analogue 2 reported previously. This novel monocarboxylic acid analogue revealed significantly higher Caco-2 cell permeability as compared to all previous compounds. Furthermore, compound 29 exhibited modest enhancement of insulin-stimulated 2-deoxyglucose uptake by L6 myocytes.

4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor

“…22 However, BQCA does contain a carboxylic acid group that is often associated with poor permeability. [34][35][36] The majority of active compounds displayed both comparable binding affinities and intrinsic efficacy to those of 1. Indeed, the lack of significant gains in affinity may be due to the nature of the binding pocket, which if it is indeed the same as that of 1, lies at the extracellular interface of the M 1 mAChR and is largely defined by aromatic residues.…”

Medicinal chemical properties of successful central nervous system drugs

“…Other factors that influence the permeability are bioisosteric replacements. 67 For example, replacement of a carboxylic acid with a tetrazole can improve permeability.…”

Microwave‐Heated Transition Metal‐Catalyzed Coupling Reactions

“…The synthesis of aryl or alkyl nitriles from halides is appreciated in medicinal chemistry as the nitriles in themselves constitute a flexible building block that can easily be converted into carboxylic acids, amides, amines, or various heterocycles [148], such as thiazoles, oxazolidones, triazoles, and tetrazoles [149]. The importance of the tetrazole group in medicinal chemistry is readily understood if one considers that it is the most commonly used bioisostere of the carboxyl group.…”