Pedro H. H. Hermkens

Solid-phase organic reactions: A review of the recent literature

Abstract Combinatorial chemistry has emerged as a powerful new technology for chemists to synthesise large numbers of compounds for biological evaluation. One of the techniques used in combinatorial chemistry is polymer supported or “solid-phase” organic synthesis. This article reviews the main chemical reactions reported between 1992-October 1995 using solid-phase support, focusing upon those suitable for synthesising small molecules. The reactions are presented in graphical format in a table according to reaction types. Examples presented include amide bond formation, aromatic substitutions, condensations, cycloadditions, diazotisation, enzymatic coupling, use of Grignard reagents, Michael additions, multiple component reactions, nucleophilic substitution, olefination, oxidations, protection/deprotection, reduction, immobilisation and cleavage. Finally, the information presented is evaluated briefly and some trends are discussed.

Solid-phase organic reactions II: A review of the literature Nov 95–Nov 96

Abstract This Report reviews literature published Nov 1996–Dec 97; it is the third in a series that summarises organic reactions performed on solid supports and is designed as an update to Tetrahedron Reports no. 394 and 418. The reactions are presented in a graphical abstract format and examples are given of the following reactions: amide formation, aromatic substitution (nucleophilic/electrophilic), cleavage, condensation, cycloaddition, deprotection/protection, Grignard and related reactions, heterocycle formation, immobilisation onto resin, Michael addition, miscellaneous, multiple component condensation, olefin formation, oxidation, reduction and substitution (nucleophilic/electrophilic). Solid-phase peptide or other oligomer synthesis and reactions using soluble polymeric supports are not included. This report ends with the discussion of some trends in the domain under consideration. This report summarises literature published during Nov 96 – Dec 97 describing solid-phase organic reactions.

The contribution of combinatorial chemistry to lead generation: an interim analysis.

In the process of finding new drug candidates medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990s synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques have resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre)clinical development towards new pharmaceutical products. Ten representative examples are given to describe the impact of ombinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre)clinical development were traced back to their source. The interim analysis showed only limited success of combinatorial chemistry approaches in terms of delivering leads. Second generation libraries appear more drug-like and focussed and may result in more compounds entering clinical studies in the future.

Non-steroidal steroid receptor modulators.

The last ten years much attention has been focused on the finding of non-steroidal ligands for steroidal nuclear receptors for reasons such as diminishing cross-reactivity to eliminate side effect profiles, changing physicochemical properties which might cause different tissue distribution profiles and altering binding modes which influence the binding of cofactors. Compounds with a selective functionality profile are referred to as selective nuclear receptor modulators (e.g., SARMs or SPRMs). In the following paragraphs non-steroidal ligands which have full or partial agonistic activity will be described for the following receptors: PR, GR, AR, LXR and FXR.

SAR study of 2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepines as progesterone receptor agonists.

We have developed a new class of progesterone receptor agonists having a tetracyclic dibenzo-oxazepine structure 1. In this paper, the synthesis and structure-activity relationships of this new class are described. This work led to the identification of potent progesterone agonists up to 1 nM activity. Substitution at positions 6, 7 and 1 has proven to be crucial for activity, indicating that probably these positions are involved in important interactions with the receptor.

Non-steroidal progesterone receptor modulators

The present invention provides compounds according to general Formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof. More particularly, the present invention provides high affinity non-steroidal compounds which are agonists, partial agonists or antagonists of the progesterone receptor.Progesterone (P4) plays an essential role in female reproduction and progesterone receptor (PR) agonists have been used in female contraceptives and in postmenopausal hormone therapy. Recent studies in women and non-human primates show that PR antagonists may also have potential as contraceptive agents and for the treatment of various gynaecological and obstetric diseases, including fibroids, endometriosis and, possibly, hormone-dependent cancers. Clinically available PR agonists and antagonists are steroidal compounds and often cause various side effects due to their functional interaction with other steroid receptors. Recently, numerous receptor-selective non-steroidal PR agonists and antagonists have emerged. This patent review will focus on the latest developments in these areas (since 2000).

Synthesis of homoallylic amines via N-acyliminium ion reactions on solid support.

The synthesis of a library of homoallylic amines is reported. The key step in the synthesis is a one-pot Nacyliminium ion coupling involving a solid phase-bound carbamate, an aldehyde and an allylsilane under Lewis acid conditions.

Peptide backbone-to-backbone cyclisation as an avenue to β-turn mimics

Abstract 1,3-Dipolar cycloaddition of the nitrone functionality of 13 and the alkene functionality of 8 yields the backbone-to-backbone cyclised peptides 14–16. The conformation of these structures is such that they are β-turn mimics. They differ in their C3 C5 stereochemistry with discrete conformational differences.

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

The steroid hormone receptors, the Androgen Receptor (AR), Estrogen Receptors (ER┙ and ER┚), Glucocorticoid Receptor (GR), Mineralocorticoid Receptor and Progesterone Receptor (PR), have been crucial targets for drug discovery even before their existence was known or understood. The drugs on the market for this sub-class of the nuclear hormone receptors constitute a significant pharmacopeia for the treatment of a vast array of conditions and ailments. Despite the breadth of drugs targeted toward this family, they remain an important target for the pharmaceutical industry. Key considerations when designing drugs for any family, beyond the on-target pharmaceutical action and safety, is to ensure specificity against related targets, exploration of the most appropriate routes of administration and desirable pharmacokinetic (PK) profiles. Developing non-steroidal modulators for the steroid receptor family has been a key strategy employed to achieve these goals, although there appears to be growing consensus that not being steroidal is insufficient to justify new drugs on its own (Hermkens et al, 2006). Unlike targeting many families, steroid hormone receptor drug discovery also has to balance the need to elicit either agonistic or antagonistic responses depending on the desired indication. The history of drug discovery for the steroid hormone receptors has tended to follow a common path, beginning with the application of purified endogenous hormone and followed by the application of the first synthetic analogs with improved PK properties or selectivity. For some of the receptors this period was followed by the design of antagonists, including non-steroidal structures. More recently, steroid hormone drug discovery has been

Identification of Ligands for the Orphan Nuclear Receptor GCNF

HTS has been executed with a luciferase reporter assay in CHO cells stably expressing an ERa/GCNF chimer. Confirmed hits could be optimized some 10 to 100 fold. Partial agonists identified during the hit optimization process behaved as antagonists in a competition based variant of the reporter assay. The latter assay format was also used to identify some full antagonists by HTS. GCNF binding of agonists and antagonists was confirmed by GCNF/cofactor interactions studies in solution.