William Leonard Mitchell

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.

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.

Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 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.

Pyridazine-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 Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral.

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.

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.

Thrombin inhibitors based on [5,5] trans-fused indane lactams

A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.

A stereoselective synthesis of cis- and trans-fused lactones via the palladium(II)-catalyzed carbonylation of organomercurials

Abstract Organomercurials 2a-c , obtained by the regioselective, Hg(II)-mediated cleavage of cyclopropyl alcohols 1a-c , are converted into the corresponding 5-membered cis -annulated lactones 3a-c via the Pd(II)-catalyzed carbonylation in the presence of p -benzoquinone. Isomeric, trans -fused lactones can be synthesized in a similar way ( 6→7 ). The carbonylation occurs under an atmospheric pressure of CO.

Molybdenum(II)-catalyzed alkylation of electron-rich aromatics with allylic acetates

Abstract The molybdenum(II) complex [Mo(CO) 4 Br 2 ] 2 has been found to catalyze allylic substitution with aromatic ethers, e.g., anisole ( 7 ), as nucleophiles. The reaction is remarkably para -selective (e.g., 7 + 8 → 11).

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

Accumulation of amyloid β (Aβ) in brain is a pathological hallmark of Alzheimers disease (AD). Aβ is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by β- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aβ 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 Aβ 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 Aβ-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 Aβ40 and Aβ42 productions, increased shorter Aβ 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 Aβ 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 Aβ peptides in AD pathogenesis.