Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors.

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration.

Pyridazine-derived γ-secretase modulators.

SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain the levels of total Aß. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.

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.

Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

Direct access to tetrahydro[1,2]diazepinones from α,ß-epoxy-N-aziridinylimines via anionic rearrangement.

A novel one-step synthetic approach to tetrahydro[1,2]diazepinones via base-promoted rearrangement of α,ß-epoxy-N-aziridinylimines, derived from α,ß-epoxyketones and N-aminoaziridines, has been developed.

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.

Asymmetric synthesis of (+)-pyrido[3,4-b]homotropane.

(+)-pyrido[3,4- b]homotropane (PHT) was efficiently constructed in 12 steps from N, N-diisopropylisonicotinamide. The synthesis features (i) RCM reaction in installing the homotropane skeleton, (ii) Snieckus ortho-lithiation of N, N-diisopropylisonicotinamide followed by acylation, (iii) Myer reduction of bulky tertiary amide to alcohol with LiBH 3NH 2, and (iv) utilization of L-glutamic acid to introduce and establish the requisite stereogenic centers.