Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aß peptides in vivo.

Accumulation of amyloid ß (Aß) in brain is a pathological hallmark of Alzheimer's disease (AD). Aß is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by ß- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aß levels. Since γ-secretase targets many different substrates, selective inhibition of its cleavage of APP is believed to be critical in order to avoid undesirable side effects. γ-Secretase modulator (GSM) shifts the cleavage site on APP and production of amyloidogenic to non-amyloidogenic Aß fragments. Since GSMs only modulate and do not block cleavage of γ-secretase substrates, they are believed less likely to produce untoward adverse reactions. Here, we report in vivo Aß-lowering profiles of a pyridazine and a pyridine-derived GSM: GSM-C (Wan et al., 2011a) and GSM-D (Wan et al., 2011b). Both compounds reduced Aß40 and Aß42 productions, increased shorter Aß fragments, and had little effect on Notch signaling (∼100-fold selective). They had excellent oral bioavailability (97.8% for GSM-C, ∼100% for GSM-D) and good brain permeability (free brain to free blood AUC ratio of 0.41 and 1.10 for GSM-C and GSM-D, respectively). Oral administration of these compounds in both acute and sub-chronic conditions reduced Aß levels in plasma and brain in rats in a dose- and time-dependent manner. Therefore, GSM-C and GSM-D represent two GSMs that are orally bioavailable and brain-permeable. They could serve as excellent tools in the investigation of the role of Aß peptides in AD pathogenesis.

Pyridine-derived γ-secretase modulators.

SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain (or increase) the levels of total Aß. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aß42 in the brain without altering Notch processing in the peripheral.

Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB(2) agonists for the treatment of inflammatory pain.

A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.

An enantiopure pseudo-C3-symmetric titanium triflate with propeller-like chirality as a catalyst for asymmetric sulfoxidation reactions.

A chiral pseudo-C(3)-symmetric titanium triflate that employs the point chirality of a single stereogenic centre to control the propeller chirality of its aryl rings has been used to catalyse an asymmetric sulfoxidation reaction.

Discovery of 1-[4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]-1-morpholin-4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic pain.

We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.

Pyridine-3-carboxamides as novel CB(2) agonists for analgesia.

We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.

Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- 5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain.

Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.

Enantiopure pseudo-C3-symmetric titanium alkoxide with propeller-like chirality.

An enantiopure amine tris(phenolate) ligand containing a single stereogenic center has been used to control the propeller-like chirality of a derived pseudo-C3-symmetric titanium isopropoxide complex with excellent levels of diastereocontrol. [structure: see text].

2,8'-disubstituted-1,1'-binaphthyls: a new pattern in chiral ligands.

The title binaphthyls 19 and 26, which are the positional isomers of 2-methoxy-2'-(diphenylphosphino)-1,1'-binaphthyl (MOP, 19) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN, 26), have been synthesized by Suzuki coupling as the key step (10 + 15-->18), followed by functional group transformations, involving C-P and C-N bond formation (18-->19 and 18-->23). Racemic intermediate 22 was resolved by co-crystallization with N-benzylcinchonidinium chloride and the absolute configuration determined by X-ray crystallography. These novel binaphthyls are configurationally stable and, as such, potentially usable as chiral ligands in asymmetric reactions. Michael addition of the glycine-derived enolate 40 to methyl acrylate, carried out in the presence of (R)-(-)-27 as the chiral phase-transfer catalyst, afforded L-glutamic acid (S)-(+)-43 of 92% ee (after hydrolysis of the primary product).

Molybdenum(II)-Catalyzed Allylation of Electron-Rich Aromatics and Heteroaromatics.

The stable, readily available molybdenum(II) complexes [Mo(CO)(4)Br(2)](2) (B) and Mo(CO)(3)(MeCN)(2)(SnCl(3))Cl (C) have been found to catalyze C-C bond-forming allylic substitution with electron-rich aromatics (e.g., 15 + PhOMe --> 62) and heteroaromatics (e.g., 15 + 36 --> 88) as nucleophiles under mild conditions (room temperature, 30 min-3 h). Remarkable is the para-selectivity for anisole, whereas phenol tends to favor ortho-substitution in certain instances. Mechanistic and stereochemical experiments are indicative of Lewis-acid catalysis rather than a metal template-controlled process.