Ian R. Baird

Synthesis of new hypoxia markers EF1 and [18F]-EF1

We report on the preparation of a hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(3-fluoropropyl)acetamide (EF1) and its 18F analog, 2-(2-nitroimidazol-1[H]-yl)-N- (3-[18F]fluoropropyl)acetamide ([18F]-EF1). Two methods for the preparation of 3-fluoropropylamine, the EF1 side chain, are described. [18F]-EF1 was prepared with a radiochemical yield of 2% by nucleophilic substitution of bromine in 2-(2-nitroimidazol-1[H]-yl)-N-(3-bromopropyl)acetamide (EBr1) by carrier-added 18F in DMSO at 120 degrees C. Our results demonstrate the preparation of clinically relevant amounts of [18F]-EF1 for use as a non-invasive hypoxia marker with detection using positron emission tomography (PET).

Nickel(II) and nickel(0) complexes containing 2-pyridylphosphine ligands, including water-soluble species

Abstract The paramagnetic, S = 1, NiX 2 L 2 (X  Cl or Br, L  PPh 3− n py n , n = 1–3), and diamagnetic NiBr 2 [d(py)pe] ( 4b ) complexes have been isolated, generally as solvates, where py = 2-pyridyl and d(py)pe = py 2 P(CH 2 ) 2 Ppy 2 . Also isolated are the diamagnetic Ni(CO) 2 (PPh 2 py) 2 ( 5 ), Ni(CO) 2 [d(py)pe] ( 7 ), Ni(PPh 2 py) 4 , Ni(PPhpy 2 ) 4 and Ni[d(py)pe] 2 , sometimes as hydrates. The complexes, except for 5 which contains paramagnetic impurities, analyze well, and have been characterized by 1 H and 31 P{ 1 H} NMR (for diamagnetic species), IR (for the carbonyls) or magnetic moment data (for the paramagnetic species). NMR evidence for in situ formation of Ni(CO) 2 (PPhpy 2 ) 2 and Ni(Ppy 3 ) 4 is also presented. Of note, NiX 2 L 2 , 4b and 7 are water-soluble, possibly because of protonation of the pyridyl-N atoms, although this remains to be established; even non-aqueous solutions of these Ni(II) species are moisture-sensitive. In contrast to Ni(PPh 3 ) 4 , at ambient conditions the NiL 4 species show little tendency to dissociate in benzene or toluene.

Unique chemistry of amino acid dithiocarbamates with Ru(III) bis-β-diketonates

Abstract The complexation chemistry of several dithiocarbamates (dtc) (KS2CProOMe, KS2CProK, KNMeIleK) with [Ru(β-diketonato)2(MeCN)2][CF3SO3] (β-diketonato=acac (2,4-pentanedionato) and dpac (1,3-diphenyl-1,3-propanedionato)) was investigated. It was discovered that the dtc underwent some unusual and unprecedented CS2-elimination chemistry to yield chelated imino or amino acidato Ru(III) complexes. For the proline case, both the KS2CProOMe and KS2CProK dtc yielded two products, the chelated dithiocarbamato complexes Ru(β-diketonato)2(dtc) (dtc=S2CProOMe or S2CProK) and the CS2-eliminated imino prolinato complexes Ru(β-diketonato)2(Pro-H2) (β-diketonato=acac (10) and dpac (14)) for which the crystal structures have been determined. For the N-methylisoleucine case, KS2CNMeIleK yielded only the CS2-eliminated amino N-methylisoleucinato complexes Ru(β-diketonato)2(NMeIle). The X-ray structure for Ru(acac)2(NMeIle) (16) was determined. The direct reaction of the amino acids (Pro or NMeIle) with [Ru(β-diketonato)2(MeCN)2][CF3SO3] yielded [Ru(dpac)2(Pro)]2 and [Ru(acac)2(NMeIle)]2, the first examples of paramagnetic μ-amino acidato bridged Ru(III) dimers which could be converted to their corresponding chelated amino acidato monomeric complexes upon treatment with base. The formal potentials of all of the Ru(III) complexes reported were determined by cyclic voltammetry.

Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication

A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.

AN EFFECTIVE SYNTHETIC ROUTE TO EF5

Abstract EF5 (a 2-nitroimidazole containing an N-(pentafluoropropyl) acetamide substituent) is a very sensitive probe for quantifying the amount of hypoxia within cells; a much improved, short step, synthetic procedure is described for EF5, whose X-ray structure is also presented.

Design of Substituted Imidazolidinylpiperidinylbenzoic Acids as Chemokine Receptor 5 Antagonists: Potent Inhibitors of R5 HIV-1 Replication

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.