Andrew P. Lightfoot

SB-656104-A: A novel 5-HT7 receptor antagonist with improved In vivo properties

A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.

The development and application of ruthenium catalysed oxidations of a hydroxamic acid and in situ Diels–Alder trapping of the acyl nitroso derivative

Ruthenium( II) complexes can be used to oxidise N-Boc-hydroxylamine in the presence of tert-butyl hydroperoxide (TBHP) to the corresponding nitroso dienophile, which is trapped by cyclohexa-1,3-diene as the hetero-Diels–Alder adduct. Direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium( IV) oxo-complex as the catalytically active species. Use of a chiral bidentate bis-phosphine derived ruthenium ligand (BINAP or PROPHOS) results in very low asymmetric induction (8 and 11%). Ruthenium( II) salen complexes also catalyse the oxidation of N-Boc-hydroxylamine in the presence of TBHP, to give the N-Boc-nitroso compound which can be efficiently trapped with a range of dienes. However, use of an enantiopure ruthenium salen complex does not produce asymmetric induction via the trapping of the intermediate acyl nitroso dienophile with cyclohexadiene, which strongly suggests that the intermediate dissociates readily from the chiral ruthenium complex involved in the oxidation step prior to Diels–Alder cycloaddition.

3 α7 Nicotinic Acetylcholine Receptor Agonists and Positive Allosteric Modulators

Publisher Summary The nicotinic acetylcholine receptors (nAChRs) are a family of cationic ligand–gated ion channels and are members of the cys-loop receptor superfamily. The α7 receptor has attracted attention as a therapeutic target for a number of disorders including schizophrenia, Alzheimers disease, and inflammation. The chapter discusses the progress in medicinal chemistry of recent α7 nAChR agonists and the advances in the discovery of α7 nAChR positive allosteric modulators. The chapter discusses α7 nAChR positive allosteric modulators. An alternative approach to activating the receptor with an exogenous agonist is the use of a positive allosteric modulator to enhance receptor function elicited by the endogenous ligand without directly activating or desensitizing the receptor. There are several positive allosteric modulators that range from proteins to small molecules, serum albumins, ivermectin, galantamine, 5-hydroxyindole, indole derivatives, sulphonamides, aminothiazoles, enaminones, thiophene amides, and ureas. There are differences in the profiles of positive allosteric modulation of the a7 nAChR, thus, there appear to be at least 2 different mechanisms of action for positive allosteric modulation: type I and type II. But, there is a considerable scope to differentiate this compound class from agonists in animal models, and ultimately in the clinic, with potential benefit to patients suffering from a number of debilitating neuropsychiatric, neurological, and inflammatory disorders.

Synthesis of C2-symmetric aza- and azaoxa-macrocyclic ligands derived from (1R,2R)-1,2-diaminocyclohexane and their applications in catalysis

Investigations have been undertaken into the synthesis of chiral derivatives of 1,4,7-triazacyclononane and 1,7-diaza-4-oxacyclononane that incorporate the C2-symmetric (R,R)-1,2-diaminocyclohexane backbone. The target ligands 17a and 17b have been prepared as their hydrochloride salts, the latter of which has been characterized by single crystal X-ray diffraction revealing an extensively hydrogen bonded polymeric network in the solid state. These investigations have shown that the formation of the fused bicyclic system in these ligands via standard Richman–Atkins macrocyclisation conditions is extremely difficult, particularly for the intermediate 16a, when three tosyl amide nitrogen atoms must be accommodated in the macrocyclic ring. In addition to these target ligands the unexpected piperazine 15 as well as the novel binucleating ligand 19 have also been prepared. Preliminary investigation into the coordination chemistry of 17b resulted in the formation of the copper(II) complex [Cu(17b)Cl2] in which the copper centre exists in the expected square-pyramidal geometry with the two chloride ions and the nitrogen donors occupying the equatorial positions and with the oxygen donor apically situated. The complex has been screened for activity and found to be a potent catalyst for two hetero-Diels–Alder reactions. The first aza-Diels–Alder reaction of imine 20 with Danishefskys diene 21 proceeds to yield the cycloadduct 22 in 94% yield. The second nitroso-Diels–Alder reaction relies on the in situ oxidation of hydroxylamine 23 to dienophile 24, catalysed by the complex in the presence of tert-butyl hydroperoxide, which is then trapped as cycloadduct 25 by cyclohexadiene in 69% yield.

Identification of a novel series of selective 5-HT7 receptor antagonists

Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.

Identification of novel α7 nAChR positive allosteric modulators with the use of pharmacophore in silico screening methods

The pharmacophore model of in house potent and selective alpha7 nAChR positive allosteric modulators is reported. The model was used to fish out commercially-available compounds from corporate 3D databases. As a result, novel alpha7 positive modulator chemotypes were identified. A rat full PK profile of a representative compound is also described.

Bis(2,6-dimethyl­pyrid­yl)iodonium dibromo­iodate

The crystal structure of the title compound, C14H18IN2+·Br2I−, isostructural with the Cl2I analogue, comprises discrete centrosymmetric cations and anions, both with linear coordination of the I atoms.

Direct evidence for a ruthenium(IV) oxo complex-mediated oxidation of a hydroxamic acid in the presence of phosphine oxide donors

Ruthenium(II) complexes can be used to oxidise N-Boc hydroxylamine the the presence of tert-butylhydroperoxide to the corresponding nitroso dienophile, which is trapped using cyclohexa-1,3-diene as the hetero-Diels-Alder adduct; direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium(IV) oxocomplex as the catalytically active species.

4,4,6-Trimethyl-2-vinyl-1,3,2-dioxaborinane: An Efficient and Selective 2-Carbon Building Block for Vinylboronate Suzuki-Miyaura Coupling Reactions

An extremely simple and efficient palladium-catalyzed coupling procedure for the synthesis of functionalized styrenes and dienes is utilized to demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be employed to selectively undergo Suzuki-Mivaura counline with a range of halide substrates.