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Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capito E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use.

Reverse cholesterol transport promoted by HDL-apoA-I is an important mechanism of protection against atherosclerosis. We have previously identified apoA-I mimetic peptides by synthesizing analogs of the 22 amino acid apoA-I consensus sequence (apoA-Icons) containing non-natural aliphatic amino acids. Here we examined the effect of different aliphatic non-natural amino acids on the structure–activity relationship (SAR) of apoA-I mimetic peptides. These novel apoA-I mimetics, with long hydrocarbon chain (C5–8) amino acids incorporated in the amphipathic α helix of the apoA-Icons, have the following properties: (i) they stimulate in vitro cholesterol efflux from macrophages via ABCA1; (ii) they associate with HDL and cause formation of pre-β HDL particles when incubated with human and mouse plasma; (iii) they associate with HDL and induce pre-β HDL formation in vivo, with a corresponding increase in ABCA1-dependent cholesterol efflux capacity ex vivo; (iv) at high dose they associate with VLDL and induce hypertriglyceridemia in mice. These results suggest our peptide design confers activities that are potentially anti-atherogenic. However a dosing regimen which maximizes their therapeutic properties while minimizing adverse effects needs to be established.

New enantiomerically pure 1,3-bis(2’-oxazolinyl)ferrocenes have been synthesized in good yields starting from 1,3-ferrocene dicarboxylic acid. Moreover, the possibility of performing a regioselective lithiation in position 2 of the disubstituted cyclopentadienyl ring of these compounds has been demonstrated.

The cyanobis(dibenzylamino)borane-mediated transformation of chiral aldehydes into the corresponding α-amino nitriles is described. Starting from these compounds short synthetic routes can be envisaged for obtaining diastereomerically pure functionalized 1,2-diamines and hydroxylated α-amino acids that are of interest as core key units of biologically active substances or as potential ligands for asymmetric catalysis. The stereochemical outcome of the aminative cyanation reaction is discussed. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Several new ligands featuring a rigid three ring skeleton have been prepared for the first time following a modular approach. Chirality has been introduced by use of an oxazoline moiety fused with a cyclopenta[b]thiophene backbone. The efficiency and stereochemical impact of these ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone was examined and enantiomeric excesses up to 79% were achieved using the ligand (R,R)-16 substituted with a methyl group at the cyclopenta moiety. Computational and ESI-mass spectral studies show that these new compounds behave as monodentate ligands towards Cu+. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a]pyrrolo[3,2-d][2]benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins.

A C-H activating Pd-catalysed alkenylation of indole is regiospecific for 2-substitution when the nitrogen carries a 2-pyridylmethyl substituent.

A nitrogen-containing superbase such as TMG was found to be an effective catalyst for the reaction between N-diphenylphosphinoyl imines and nitroalkanes. Exploiting a protocol that avoids the use of any solvent also during workup procedure, we synthesized a series of beta-nitroamines in excellent yields and high diastereomeric ratios. These results, combined with the capability of the indium in conjunction with Zn as the stoichiometric reducing agent to perform in aqueous medium reduction of the nitro group under mild reaction conditions, led us to devise a three-step, one-pot synthesis of a range of 1,2-diamines, making use of environmentally friendly procedures in the various steps.

A series of new chiral oxazoline-1,3-dithianes has been easily synthesized and used as ligands for asymmetric catalysis. The conjugate addition of Et 2 Zn to enones resulted in ees of up to 69%, whereas the Pd-catalyzed allylic alkylation led to the expected products in almost quantitative yields and up to 90% enantioselectivity. The ligand’s conformation has been explored using a combination of X-ray and NMR measurements, indicating the presence of a remarkable anomeric effect, which accounts for the preference of the oxazoline ring for the axial location.

N,N-Disubstituted α-aminonitriles undergo Bruylants reaction under Barbier and Reformatsky conditions with activated halides, in the presence of zinc and 10 mol% HOAc. The high yields and the simple operational conditions make this reaction an appealing, approach to N,N-disubstituted homoallylamines and β-aminoesters.

A straightforward procedure for the regio- and stereoselective synthesis of alpha-hydrazino ketones is described. Manganese enolates and manganese enamines derived from ketones and from the corresponding N-sulfinylimines react with azodicarboxylate esters (DTBAD and DEAD) in a regioselective fashion to afford in good to excellent yields the kinetic alpha-hydrazino ketones as sole or highly prevalent products. When enantiopure N-sulfinyl manganese enamines were used the stereoselectivity of these reactions ranged from 40% to 68% ee.

Enantiomerically pure 2-hydroxyalkyl, 2-aminoalkyl and 2-iminoalkyl ferrocenyl p-tolylsulfides are easily prepared in good yields and with complete diastereocontrol from (S)-(2-p- tolylthio)ferrocencarboxyaldehyde. This aldehyde provides also an easy access to the first enantiomerically pure planar chiral ferrocenyl cyanohydrin. The absolute configuration of the new stereocenters has been determined by single-crystal X-ray analysis.