Rainer E. Martin

Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities

This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of physical and ADME properties of many lead structures in drug‐discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chemistry. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivatives are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug‐discovery research, but also to the development of new crop‐protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine‐based organocatalysis.

Determination of End-to-End Distances in a Series of TEMPO Diradicals of up to 2.8 nm Length with a New Four-Pulse Double Electron Electron Resonance Experiment

A four-pulse version of the pulsed double electron electron resonance (DEER) experiment has been applied to a series of TEMPO diradicals with well-defined interradical distances ranging from 1.4 to 2.8 nm (see picture). The new pulse sequence allows broad distributions of electron-electron distances to be measured without dead-time artifacts.

A Convenient Photocatalytic Fluorination of Unactivated CH Bonds

Fluorination reactions are essential to modern medicinal chemistry, thus providing a means to block site-selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated CH bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of unactivated CH bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N-fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.

Photocatalytic synthesis of allylic trifluoromethyl substituted styrene derivatives in batch and flow.

A cobalt-catalyzed photochemical synthesis of allylic trifluoromethanes from styrene derivatives using 2,2,2-trifluoroethyl iodide is described. The method complements existing approaches, providing an alternative bond construction strategy to access these compounds. The process may be conducted in continuous mode in a novel photochemical flow reactor, resulting in a notable productivity increase.

Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.

Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes

Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.

Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist.

According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved.

Monodisperse Poly(triacetylene) Oligomers Extending from Monomer to Hexadecamer: Joint Experimental and Theoretical Investigation of Physical Properties

A series of monodisperse Et3-Si-end-capped poly(triacetylene) (PTA) oligomers ranging from monomer to hexadecamer was prepared by a fast and efficient statistical deprotection-oxidative Hay oligomerization protocol. The PTA oligomers exhibit an increasingly deep-yellow color with lengthening of the pi-conjugated backbone, feature excellent solubility in aprotic solvents, and exhibit melting points up to > 22 degrees C for the hexadecameric rod. This new dramatically extended oligo(enediyne) series now enables to investigate the evolution of the physico-chemical effects in PTAs beyond the linear 1/n versus property regime into the higher oligomer region where saturation becomes apparent. We report the results of joint experimental and theoretical studies, including analysis of the 13C NMR spectra, evaluation of the linear (UV/ Vis) and nonlinear [third-harmonic generation (THG) and degenerate four-wave mixing (DFWM)] optical properties, and characterization of the redox properties with cyclic and steady-state voltammetry. Up to the hexadecameric rod, an increasingly facile one-electron reduction step is observed, showing at the stage of the dodecamer, a leveling off tendency from the linear correlation between the inverse number of monomer units and the first reduction potential. The effective conjugation length (ECL) determined by means of UV/Vis spectroscopy revealed a pi-electron-delocalization length of about n = 10 monomeric units, which corroborates well with the oligomeric length for which in the 13C NMR spectrum C(sp2) and C(sp) resonances start to overlap. Third-harmonic generation (THG) and degenerate four-wave mixing (DFWM) measurements revealed for the second-order hyperpolarizability gamma a power law increase gammma-alpha-n(a) for oligomers up to the octamer with exponential factors a= 2.46+/-0.10 and a=2.64+/-0.20, respectively, followed by a smooth saturation around n = 10 repeating units. The power law coefficient a calculated with the help of the valence effective Hamiltonian (VEH) method combined to a sum-over-states (SOS) formalism corroborates well with the values found by both THG and DFWM experiments. Up to the PTA heptamer, INDO (intermediate neglect of differential overlap)-calculated gas-phase ionization potentials and electron affinities obey a linear relationship as a function of the inverse number of monomer units displaying a strong electron-hole symmetry. The onset of saturation for the electron affinity is calculated to occur around the octamer, in accordance with experimentally obtained results from electrochemical measurements.

Synthesis of a Drug-Like Focused Library of Trisubstituted Pyrrolidines Using Integrated Flow Chemistry and Batch Methods

A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical parallel synthesis techniques, and thus exemplifies the impact of integrating innovative enabling tools within the drug discovery process.

Third-order nonlinear optical properties of in-backbone substituted conjugated polymers

We present an alternative approach to tune the third-order nonlinear optical properties of organic molecules by inserting a functional group into the path of the π-electron conjugation instead of at its ends. We show that this scheme has a beneficial influence on the second-order hyperpolarizability for short molecules, but that in two instances where such molecules were polymerized into longer molecules the overall hyperpolarizability is reduced.