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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials. KEYWORDS: MAPK pathway, MEK, cancer, kinase inhibitor, XL518, GDC-0973 T he MAPK cascade, or mitogen-activated protein kinase signal transduction pathway, is a mechanism commonly subject to dysregulation in cancer, and constitutive or highly upregulated signaling is a frequent hallmark of oncogenic transformation and progression. Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations. 5,6 Inhibitors of MEK have demonstrated efficacy against malignant tumors characterized by mutations in either RAS or Raf in preclinical models, and early development candidates including GSK1120212, In some tumors, activation of both the RAS driven ERK/ MAPK cascade and the PI3K-Akt pathway is observed, resulting in degenerate and convergent oncogenic signals, and upregulation or constitutive PI3K pathway activation is associated with resistance to MEK inhibitor single agent treatment.10 Several combination approaches using inhibitors of mTor, PI3K, Akt, and Raf have more recently been validated in preclinical models and are being pursued clinically. Herein, the discovery of XL518 (GDC-0973) (1), a potent and selective MEK inhibitor, is described. XL518 is currently in early stage clinical testing as both a single agent and in combination with the class I PI3K inhibitor GDC-0941. 11Our goal at the outset was the identification of a potent and selective MEK inhibitor with sustained duration of efficacy suitable for qd dosing and an optimized safety profile relative to clinical precursors. The diphenylamine series disclosed by the Pfizer/Warner Lambert groups served as a starting point for our effort. A key aspect tha...

A versatile synthesis of 2-arylpyrroles and 2-arylindoles is described based on the use of either N-(Boc) pyrrole-2-boronic acid or N-(Boc) indole-2-boronic acid as components for Suzuki coupling.We have described the design of a series of 2,5-disubstituted pyrroles 1 as selective dopamine D 3 receptor antagonists, the synthesis of which required 2-arylpyrroles 2 as key intermediates. 1 Initial approaches to 2 involved reaction of the appropriate benzoyl chloride 3 with Grignard reagent 4 and subsequent treatment with ammonium acetate in a modification of a known procedure. 2 This method is, however, incompatible with the presence of acidic protons or basic nitrogens in 2, and each desired substitution pattern requires repetition of a lengthy reaction sequence. An alternative strategy based on palladium-catalysed aryl cross-coupling methodology offered promise as a shorter, direct and more flexible route and here we describe the successful implementation of this approach.The few literature examples of palladium-catalysed cross coupling involving metallated pyrroles have mainly described the use of magnesium, zinc and tin species. 3,4,5 The use of N-(triisopropylsilyl)pyrrole-3-boronic acid as a Suzuki coupling substrate has been reported, 5 and more recently, the coupling of N-(Boc) pyrrole-2-boronic acid 6 5 to a pyrrole-2-triflate has been described. 7 The use of N-(phenylsulfonyl) pyrrole-2-boronic acid in Suzuki couplings has also been reported. However, the synthesis of this boronic acid starting material proceeds in only 7.5% yield. 8The wide availability of aryl halides, together with the reported stability of 5 suggested a general methodology for the synthesis of 2-arylpyrroles. The N-Boc pyrrole 5 can be readily prepared on a 20 g scale according to the procedure of Martina et al. 6 and the cross coupling reactions of 5 with a range of aryl halides were carried out using the Gronowitz conditions. 9 A mixture of the appropriate aryl iodide or bromide (ArX), tetrakis-(triphenylphosphine)palladium(0) (5 mol%) and 5 (1.4 equivalents) in 1,2-dimethoxyethane, with an excess of aqueous sodium carbonate as base, was heated at reflux for 0.5-18 h to give the corresponding N-Boc aryl pyrroles 6 10 (Scheme 1). The results of the study are summarised in Table 1. For the simple monosubstituted and unsubstituted aryl halides (entries 1-7), a trend was observed towards greater reactivity with increased electron deficiency of the Ar group. In the case of Ar = Ph, iodobenzene (entry 1) gave a cleaner reaction than bromobenzene (entry 2).In all instances the major competing side reactions were deboronation of 5 to give N-(Boc) pyrrole and production of the homodimer 7. 11 The 2-methoxy substituted halides (entries 8-11) gave particularly high yields, possibly due to participation by the 2-methoxy group in the coordination of the intermediate arylpalladium species, and this methodology proved to be compatible with the presence of acidic NH residues (entries 9 and 10) and with the presence of a basic nitrogen centre (entry ...

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.

We report the first example of enantioselective and diastereoselective aldehyde additions of propargyl acetate to aldehydes using the methodology recently reported from our laboratories. Subsequent O-silyl protection, Pd-catalyzed isomerization, AcOH addition, and hydrolysis result in optically active gamma-hydroxy alpha,beta-unsaturated aldehydes as powerful building blocks. Reaction: see text.

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