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The enantioselective catalytic epoxidation of unfunctionalized alkyl and aryl olefins was conducted using titanocene and niobocene peroxide complexes incorporating a C 2 -symmetrical binaphthylcyclopentadienyl ligand (BpDMCp). Enantiomeric excesses up to 20% and activities up to 55 turnovers were obtained with the application of our chiral bis(binaphthylcyclopentadienyl)-derived metallocenes. A significant decrease in the enantioselectivity for the epoxidation of trans -3-hexene was observed when the metal was changed from titanium to niobium in these binaphthyl-derived C 2 -symmetrical complexes. The preparation of the bis(binaphthylcyclopentadienyl)-chloroniobium peroxide complexes and bis(indenyl)chloroniobium peroxide is described.

Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.

The asymmetric catalytic epoxidation of various unfunctionalized alkyl and aryl alkenes has been accomplished using the new C 2 -symmetrical 1,1′-binaphthyl-2,2′-dimethylene-bridged ansa -Bis(1-indenyl)titanium dichloride complex. Enantiomeric excesses of 22% and activities up to 61 turnovers were observed using the (R)(−)-BpDM-(1-ind) 2 TiCl 2 catalyst.

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.

Publisher Summary This chapter focuses on high-affinity niacin receptor GPR109A Agonists. Niacin (nicotinic acid) at high doses favorably modulates the human lipid profile by elevating high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and lipoprotein a [Lp(a)]. Specifically, the ability of niacin to increase HDL-C (∼20%) is greater than any other drug in the market. As such niacin is considered a broad-spectrum lipid-lowering drug. With well-established animal models to evaluate vasodilation and free fatty acids (FFA) reduction, several compounds have been profiled in vivo and they indeed displayed improved TIs relative to niacin. In addition, these models appeared to correlate to humans as two candidates including both MK-0354 and INCB-19062 that showed excellent FFA reduction accompanied by minimal flushing in humans. It is conceivable that GPR109A is still involved in the vascular inflammation pathway related to the antiatherosclerotic effect of niacin. To further investigate the therapeutic potential of GPR109A agonists in cardiovascular diseases or metabolic disorders, it is necessary to further elucidate the mechanism of action of niacin and the pharmacology of GPR109A.

4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.

Nicotinic acid (NA) has been used as a drug to treat dyslipidemia for50 years. In outcome clinical trials, NA displayed remarkable efficacy in patients with cardiovascular diseases by modifying lipid profiles that results in reduced morbidity and mortality. On the other hand, NA induces vasodilation (flushing) that undermines treatment compliance. In addition, high-dose treatment is required presumably owing to the poor pharmacokinetic properties of NA. The identification of the high-affinity NA receptor, namely G-protein coupled receptor 109A (GPR109A), led to further understanding of the pharmacological effects of NA and discovery of compounds that are potentially superior in efficacy yet devoid of NA's adverse effects.This review focuses on the endeavors of several pharmaceutical companies to discover and develop GPR109A agonists. Representative compounds of each series in patent literature since 2005 are highlighted.Highly potent GPR109A agonists with minimal flushing effects and robust free fatty acid reduction have been identified. Despite the failure of the partial agonist MK-0354 to achieve efficacy in a Phase II clinical trial, at least three other GPR109A agonists have been evaluated in clinical trials. The upcoming clinical data would be critical to validate the therapeutic utility of this receptor.

The palladium-catalyzed Suzuki-Miyaura coupling of pyridyl-2-boronic esters provided an efficient approach to useful biaryl building blocks containing a 2-pyridyl moiety. The convenient reaction protocol demonstrates its potentially wide applications in medicinal chemistry.

Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.

The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.

Pyrazolopyrimidines were discovered as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. In addition to its intrinsic activity, compound 9n significantly enhances nicotinic acid binding to the receptor, thereby potentiating the functional efficacy of nicotinic acid.

A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.

Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.

A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.

The gold(I)-catalyzed regioselective cyclizations of silyl ketene amides or carbamates with alkynes were utilized to construct cyclopentanes or dehydro-delta-lactams.

A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.

[reaction: see text] A mild and efficient alpha-heteroarylation of simple esters and amides was developed via nucleophilic aromatic substitution. The choice of NaHMDS in toluene gave the best results. A tandem alpha-heteroarylation and hydroxylation protocol using air as the oxidant afforded tertiary alcohols in good yields.

Imidazo[1,2-a]pyridyl N-arylpyridazinones were hybridized from the classic pyridinylimidazoles and the more recent dual hydrogen bond acceptors, resulting in a new structural class of selective p38 MAP kinase inhibitors.

Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.

A medicinal chemistry program on the nodulisporic acid chemical class, guided by an artificial membrane flea-feeding assay, has recently identified permissive and nonpermissive regions of the pharmacophore for exploitation against fleas. This pathway was validated when several promising compounds from this program were administered orally to dogs at 15.0 mg/kg and found to have90% flea activity for 2 wk. To determine if a surrogate insect assay would have provided the same guidance, a nodulisporic acid analog series was examined in both a Lucilia sericata larval assay and an artificial membrane flea-feeding assay using Ctenocephalides felis. Results from both insect assays were concordant in that even subtle chemical modification or substitution to the left-hand side of the nodulisporic acid pharmacophore resulted in substantial loss of insecticidal activity. Both assays were also in general agreement that the only modifications to the pharmacophore that did not result in loss of activity occurred to the C-8 side chain on the right-hand side of the molecule. Although there was good agreement between the 2 assays on the general regions of the pharmacophore, there was variance on individual compounds in the mono- and disubstituted amide series from the C-8 side chain. For example, the L. sericata assay showed several analogs from this subclass to possess similar activity to the parent acid, whereas the membrane assay indicated superior activity against fleas relative to the same parent. Consequently, although there was substantial general agreement between the assays, it was concluded that finer optimization of a lead compound should be done against the target parasite, even if it is ex vivo, as early as possible in a medicinal chemistry program.

Recently isolated at Merck, apicidin inhibits both mammalian and protozoan histone deacetylases (HDACs). The conversion of apicidin, a nonselective nanomolar inhibitor of HDACs, into a series of picomolar indole-modified and parasite-selective tryptophan-replacement analogues is described within this structure-activity study.

An efficient degradation of apicidin's ketone-containing side chain to two common intermediates (the C7-aldehyde and the C8-methyl ester) is described. From these intermediates, a series of potent mechanism-based histone deacetylase inhibitors was prepared to facilitate biochemical studies.

Delivery of siRNA to the RISC complex for therapeutic effect remains a difficult challenge. One approach investigated by Merck is siRNA delivery via an artificial membrane. By encapsulating the siRNA in membrane, these so-called lipid nanoparticles (LNPs) are able to survive in plasma long enough to reach their target, e.g. livers cells. Multicomponent LNPs are investigated through large scale molecular dynamics (MD) simulations. Specific LNP formulations comprising cholesterol, phospholipids, PEG-lipid and a variety of cationic lipids have been studied. The MD simulations were carried out using the GROMACS united atom potentials in the NPT ensemble with the temperature set at 310K. Each model LNP was simulated for ∼ 150ns. These large simulations were accomplished with 128 processors on Merck's Cray-XT5 and the support of MRL IT. Average surface areas (SA), lipid conformations and lipid order parameters are calculated from steady state trajectories for each of the cationic lipids. Simulations results can be compared to experimental observables such as ApoE binding and fusogenicity, providing an atomistic level hypothesis of measured differences. For example, larger SA/lipid appears to correlate with stronger ApoE binding.

A novel fungal metabolite, apicidin [cyclo( N - O -methyl- l -tryptophanyl- l -isoleucinyl- d -pipecolinyl- l -2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin’s antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation–deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

The synthesis of a full series of analogs 2b-k of deglycobleomycin A2 (2a) containing systematic variations in the linker domain of bleomycin A2 (1) is described. The agents 2b-k, which are not accessible through structural modification of 1 or 2a, constitute key substructure analogs incorporating deep-seated structural modifications in the linker domain capable of delineating the contribution of the individual backbone substituents to the DNA cleavage efficiency, characteristic DNA cleavage selectivity, and double strand to single strand DNA cleavage ratio. The comparative examination of the DNA cleavage properties of the Fe(II) and Fe(III) complexes of 2a-k upon activation by O2-thiol or H2O2, respectively, revealed several characteristic features and trends. First, none of the substituents affect the characteristic 5'-GC, 5'-GT > 5'-GA DNA cleavage selectivity of bleomycin A2. In contrast, an exceptionally prominent role for the L-threonine substituent and an important role for the C4-methyl substituent of the (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid subunit were observed on the DNA cleavage efficiency of the agents. Similarly, the L-threonine substituent was found to substantially increase the ratio of double strand to single strand DNA cleavage events (2-3 times). In a w794 DNA cleavage assay, shortening the linker region by two carbons resulted in an exceptionally large reduction in DNA cleavage efficiency (125 times) and provided an agent that was only 1.3 times more effective than Fe(III) indicating that this deep-seated modification essentially destroys the DNA cleavage capabilities of the agent. The L-threonine substituent contributes in an exceptional manner, and its removal resulted in a 25 times reduction in DNA cleavage efficiency. A substantial contribution was observed for the C4-methyl group on the 4-aminobutanoic acid subunit and its removal resulted in a 7 times reduction in DNA cleavage efficiency. Little effect for the C3-hydroxyl and C2-methyl substituents on the 4- aminobutanoic acid subunit was observed (0-2.5 times) and even their inversion of stereochemistry had little impact on DNA cleavage efficiency or selectivity. Notably, the magnitude of the previously unappreciated L-threonine substituent contribution to the DNA cleavage efficiency and on the ratio of double to single strand DNA cleavage events is the largest effect observed to date including the well recognized disaccharide potentiation (6 times) of the DNA cleavage properties. Consequently, the past role and relative importance of the L-threonine subunit and substituent has been underestimated. Moreover, the cumulative effect of the two important linker chain substituents clearly illustrate that the functional role of this domain is much more important than its simply serving as a linker.

The asymmetric preparation and metallation of binaphthylcyclopentadiene 1 is described. The key step in this four step synthesis is an asymmetric nickel-catalyzed coupling reaction.