Timothy F. Herpin

Novel solid-phase synthesis of 1,5-benzothiazepine-4-one derivatives

Abstract A new solid-phase efficient route to 1,5-benzothiazepine-4-one derivatives is reported. The synthesis exploits the variety of halo-nitrobenzene derivatives available and the facile substitution of the benzamide nitrogen. A wide range of derivatives can be obtained in excellent purity.

Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y1 antagonists.

Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.

Deprotection of N-alloc amines by Pd(0) /DABCO: an efficient method for in situ peptide coupling of labile amino acids

A highly efficient one-pot deprotection/peptide coupling protocol of N-Alloc amino acids with activated N-Boc or N-Fmoc amino acids was developed in solution and on solid phase. DABCO was found to be especially effective for the deprotection of the N-Alloc group, resulting in short reaction times (10–20 min) and allowing the coupling of amino acids that are unstable in unprotected forms.

Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds

Publisher Summary This chapter reviews the principle of directed sorting and presents two detailed examples of its application in drug discovery: (1) the synthesis of piperazine-2 carboxamide derivatives and (2) the synthesis of benzothiazepine derivatives. The directed sorting approach (or mix-and-sort approach) uses small synthetic objects, called microreactors that are equipped with a readable encoding system. Typically the synthetic objects can be resin beads placed in a semi-porous container, a grafted polymer surface, or large plugs of resin beads. The coding system can be a radiofrequency tag (RF-Tag), a two-dimensional (2D) optical bar code, a color scheme, or a spatial array. Several types of equipment can be used to prepare combinatorial libraries through the directed sorting technique. The Accutag system is well suited to prepare libraries of 10-10,000 compounds, whereas the Nanokan system is useful for 10,000-100,000 member libraries. For small libraries, the color-coded MicroKans can be used.

Synthesis and diversity analysis of lead discovery piperazine-2-carboxamide libraries

A Lead Discovery Library ofpiperazine-2-carboxamide derivatives was produced forgeneral screening. This paper discloses two novelsolid phase synthetic routes used to produce 15 000single compounds via the Irori directed sortingtechnique. Computational methods such as reagentclustering and library profiling were used to maximizereagent diversity and optimize pharmacokineticparameters. The results of a four center pharmacophoreanalysis revealed the added diversity gained by usingtwo independent synthetic routes.