Daniel Zimmerli

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.

Selective GlyT1 Inhibitors: Discovery of [4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a Promising Novel Medicine To Treat Schizophrenia

The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery.

The synthesis of a collection of 3-substituted indole derivatives incorporating partially fluorinated n-propyl and n-butyl groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aqueous solubility, and metabolic stability. The experimental observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit molecular design in medicinal chemistry and, more broadly, in life as well as materials sciences.

Strain-Accelerated Formation of Chiral, Optically Active Buta-1,3-dienes†

The formal [2+2] cycloaddition-retroelectrocyclization (CA-RE) reactions between tetracyanoethylene (TCNE) and strained, electron-rich dibenzo-fused cyclooctynes were studied. The effect of ring strain on the reaction kinetics was quantified, revealing that the rates of cycloaddition using strained, cyclic alkynes are up to 5500 times greater at 298 K than those of reactions using unstrained alkynes. Cyclobutene reaction intermediates, as well as buta-1,3-diene products, were isolated and their structures were studied crystallographically. Isolation of a rare example of a chiral buta-1,3-diene that is optically active and configurationally stable at room temperature is reported. Computational studies on the enantiomerization pathway of the buta-1,3-diene products showed that the eight-membered ring inverts via a boat conformer in a ring-flip mechanism. In agreement with computed values, experimentally measured activation barriers of racemization in these compounds were found to be up to 26 kcal mol(-1) .

Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties.

The modulation of pharmacologically relevant properties of N‐alkyl‐piperidine‐2‐carboxamides was studied by selective introduction of 1–3 fluorine atoms into the n‐propyl and n‐butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non‐fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine‐2‐carboxamide core is chiral, pairs with enantiomeric N‐alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.

Discovery of benzoylisoindolines as a novel class of potent, selective and orally active GlyT1 inhibitors

Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.

Replacement of Water Molecules in a Phosphate Binding Site by Furanoside‐Appended lin‐Benzoguanine Ligands of tRNA‐Guanine Transglycosylase (TGT)

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.

Sugar Acetonides are a Superior Motif for Addressing the Large, Solvent-Exposed Ribose-33 Pocket of tRNA-Guanine Transglycosylase

The intestinal disease shigellosis caused by Shigella bacteria affects over 120 million people annually. There is an urgent demand for new drugs as resistance against common antibiotics emerges. Bacterial tRNA-guanine transglycosylase (TGT) is a druggable target and controls the pathogenicity of Shigella flexneri. We report the synthesis of sugar-functionalized lin-benzoguanines addressing the ribose-33 pocket of TGT from Zymomonas mobilis. Ligand binding was analyzed by isothermal titration calorimetry and X-ray crystallography. Pocket occupancy was optimized by variation of size and protective groups of the sugars. The participation of a polycyclic water-cluster in the recognition of the sugar moiety was revealed. Acetonide-protected ribo- and psicofuranosyl derivatives are highly potent, benefiting from structural rigidity, good solubility, and metabolic stability. We conclude that sugar acetonides have a significant but not yet broadly recognized value in drug development.

A Straightforward and Efficiently Scaleable Synthesis of Novel Racemic 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives

Novel and straightforward syntheses (3-5 steps, high yields) of racemic diazaspiropiperidine derivatives based on the Michael addition of pipecolate-derived enolates to a range of nitroalkenes have been developed. The reaction has been shown to have a general scope and can be conducted on a preparatively useful scale. Isolation and identification of diazaspiropiperidine enantiomers was efficiently achieved using normal phase chiral HPLC.