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Pharmacokinetic properties of our first-generation HIF-2α antagonist PT2385, including modest solubility, resulted in a high recommended phase 2 dose (RP2D) of 800 mg BID and motivated the pursuit of novel scaffolds which could improve solubility and formulation parameters with the goal of improved pharmacokinetics. Herein we disclose our successful efforts to identify such HIF-2α antagonists through an optimization strategy characterized by: (1) increasing the fraction of sp3 hybridized carbons (Fsp3), (2) replacing the aromatic portion of the indane core with pyridine heterocycles, and (3) improving a putative Olp → π*Ar interaction, an underutilized electrostatic contact in medicinal chemistry. These efforts emphasize the importance of employing multiple strategies in parameter optimization. In isolation, modifications to areas (1) and (2) improved solubility, but with the compromise of reduced potency. In area (3), understanding the importance of an Olp → π*Ar interaction, as documented through a wealth of crystal structures and retrospective calculations, proved essential in guiding SAR and identifying the trifluoromethyl group as a suitable replacement of the sulfone. Only by combining these three strategies could inhibitors with substantially improved solubility and comparable potency be discovered. Finally, the overall improvement in pharmacokinetic properties of the newly identified inhibitors is highlighted through a battery of ADME and in vivo data, including use of pharmacodynamic biomarkers indicative of HIF-2α antagonism.

Supplementary method includes detailed experimental procedure for the synthesis of PT2385. Supplementary Figures 1-7 - Lack of cytotoxicity of PT2385 in cultured 786-O and A498 cells (1); PT2385 pharmacokinetics in CD-1 mice (2); Inhibition of HIF-2� gene expression and circulating hVEGFa in A498 mouse xenograft model after treatment with PT2385 (3); HIF-2� mRNA and protein levels in 786-O cells in vitro after treatment with PT2385 (4); Levels of HIF-1� and HIF-2� in patient-derived xenograft tumors (5); Body weight of mice in efficacy studies treated with either vehicle, PT2385 or sunitinib (6); Binding of PT2385 to rat HIF-2� as determined by ITC and inhibition of mouse kidney EPO gene expression with PT2385 treatment (7).

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.

A fuzzy compactum in a space X is an upper semi-continuous map f : A → [ 0 , 1 ] from a nonempty compact subspace A ⊂ X to the unit closed interval [ 0 , 1 ] such that { x ∈ A : f ( x ) > 0 } is dense in A. In this paper, we investigate the topological structure of the space K e ( X ) of fuzzy compacta of a separable metric space X with the Hausdorff metric. In particular, we prove that K e ( X ) ≈ l 2 if X is an infinite, locally compact, locally connected, connected and separable metric space.

The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.

HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel–Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.

In this paper, we characterize stratifiable (or semi-stratifiable) spaces, and monotonically countably paracompact (or monotonically countably metacompact) spaces by expansions of locally upper bounded semi-continuous poset-valued maps. These extend earlier results for real-valued Locally bounded functions., Comment: 15 pages

For a finite tree T and its endpoint v, we can define a natural partial order ≤ such that v is the greatest element in T. For a compact metric space X and a continuous map f : X → T , let ↓ f = { ( x , t ) : t ≤ f ( x ) } and ↓ C ( X , T ) = { ↓ f : f is continuous from X to T } . We investigate the subspace ↓ C ( X , T ) of the family of all non-empty closed sets in X × T with the Hausdorff distance. The following result is proved: For every non-degenerate Peano continuum X and a tree T with n segments { S 1 , S 2 , ⋯ , S n } , ↓ C ( X , T ) ≈ ⨁ i = 1 n ↓ C U B ( S i ) , where C U B ( S i ) = { f ∈ C ( X , T ) : max ⁡ f ( X ) ∈ S i } . Moreover, every ↓ C U B ( S i ) is contractible space. As a conclusion, ↓ C ( X , T ) has n connected component.

N-K 2 Ti 4 O 9 /g-C 3 N 4 /UiO-66 ternary composites were successfully synthesized by a solvothermal method, and were characterized by powder X-ray diffraction, UV–vis diffuse reflectance spectroscopy, the valence band X-ray photoelectron spectroscopy, field emission transmission electron microscopy, photoluminescence emission spectra and N 2 adsorption-desorption. Photocatalytic activities of N-K 2 Ti 4 O 9 , g-C 3 N 4 , UiO-66, N-K 2 Ti 4 O 9 /g-C 3 N 4 binary composites and the ternary composites were investigated by the degradation of Rhodamine B (RhB) under visible light irradiation. The results show that the ternary composites exhibit higher photocatalytic activity as compared with the binary composites and the pure materials. The synergistically enhanced photocatalytic activity of the ternary composites is due to coupling direct solid-state Z-scheme N-K 2 Ti 4 O 9 /g-C 3 N 4 heterojunction with high adsorption capacity of UiO-66 for RhB.

PbBiO2Br/UiO-66-NH2 composites synthesized by a facile solvothermal method have a core–shell structure with UiO-66-NH2 forming the shell around a PbBiO2Br core. Their photocatalytic activities in the degradation of Rhodamine B (RhB) dye solution and colorless phenol solution under visible light irradiation were investigated. For both model organic pollutants, the PbBiO2Br/UiO-66-NH2 composites exhibit higher photocatalytic activity than the pure components. This synergistic effect is due to the high adsorption capacity of UiO-66-NH2 and the compounding induced an enhanced separation efficiency of photogenerated electron–hole pairs. The composite with a 3 : 2 mass ratio of PbBiO2Br to ZrCl4 exhibits the highest photocatalytic activity for RhB degradation, in which trapping experiments confirm that the photogenerated holes and O2˙− radicals are the main active species.

HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*

N-K 2 Ti 4 O 9 /MIL-101 composites were successfully synthesized by a facile hydrothermal method, and were characterized by powder X-ray diffraction, UV–vis diffuse reflectance spectroscopy, the valence band X-ray photoelectron spectroscopy, field emission transmission electron microscopy, photoluminescence emission spectra, N 2 adsorption–desorption and thermogravimetric analysis. Photocatalytic activities of N-K 2 Ti 4 O 9 , MIL-101 and the composites were investigated by the degradation of Rhodamine B (RhB) under visible light irradiation. The results show that the composites exhibit higher photocatalytic activity as compared with the pure materials. The synergistically enhanced photocatalytic activity of the composites is due to big adsorption capacity of MIL-101 and high separation efficiency of photogenerated electron-hole pairs through interfaces between N-K 2 Ti 4 O 9 and MIL-101.

In the present study, MIL-101(Cr) and Bi25FeO40 were successfully synthesized by hydrothermal method, and were wrapped by polythiophene (PTH) to form a new composite catalyst, Bi25FeO40/MIL-101/PTH. The pure materials and composite were fully characterized by X-ray diffraction, transmission electron microscopy and UV–vis spectrophotometer. Moreover, the photocatalytic activities of the catalysts were evaluated by measuring the degradation of Rhodamine B under visible light. The results show that the composites exhibit better photocatalytic activities than pure materials and P25, which can be ascribed to the big adsorption capacity of MIL-101(Cr) and the rapid transferring and separation of photogenerated charge carriers through PTH connected interface between MIL-101(Cr) and Bi25FeO40.

Herein, two zirconium(IV)-based MOFs UiO-66 and UiO-66-NH2 had been successfully prepared by a facile solvothermal method and were characterized by X-ray diffraction (XRD), field emission transmission electron microscopy (FETEM), N2 adsorption–desorption (BET), X-ray photoelectron spectroscopy (XPS), and zeta potential. They exhibit small size, large surface area, and can remove cationic dyes from aqueous solution more effectively than anionic dyes. This adsorption selectivity is due to the favorable electrostatic interactions between the adsorbents and cationic dyes. Furthermore, owing to the individual micropore structure of UiO-66-NH2 and its more negative zeta potential resulted from the charge balance for the protonation of –NH2, UiO-66-NH2 displays much higher adsorption capacity for cationic dyes and lower adsorption capacity for anionic dyes than UiO-66.

In this study, a novel composite containing a Cr based metal–organic framework (MOF), MIL-101 and BiVO4 was successfully synthesized by hydrothermal method, and was fully characterized by X-ray diffraction, transmission electron microscopy, thermogravimetric analysis, UV-vis diffuse reflectance absorption spectra and photoluminescence emission spectra. Moreover, the photocatalytic activities of BiVO4/MIL-101 composite and the pure materials were evaluated by measuring the degradation of Rhodamine B under visible light. The results show that the composite exhibits better photocatalytic activities than pure materials, which can be ascribed to the big adsorption capacity of MIL-101 and the enhanced separation of photogenerated charge carriers from assembly of MIL-101 on BiVO4. The synergistic effect between BiVO4 and MIL-101 was evaluated by the proposed synergistic factor, which is bigger than 1 for various ratios of BiVO4 to MIL-101, suggesting there exists positive interactions between pure materials for enhancing photocatalytic activities.

For a Tychonoff space X , denote ↓ C F ( X ) to be the set of hypographs of all continuous functions from X to [ 0 , 1 ] equipped with the Fell topology. We prove Main Theorem Let X be a Tychonoff space satisfying the following conditions: (i) ↓ C F ( X ) is metrizable; (ii) X is a non-discrete k-space; (iii) X has a dense set of isolated points; (iv) the set of non-isolated points of X is not compact. Then ↓ C F ( X ) is homeomorphic to the subspace c 0 ∪ ( Q ∖ Σ ) of Q, where Q = [ − 1 , 1 ] N is the Hilbert cube, Σ = { ( x n ) ∈ Q : sup n ∈ N ⁡ | x n | 1 } and c 0 = { ( x n ) ∈ Σ : lim n → ∞ ⁡ x n = 0 } .

Potent imidazopyridine-based inhibitors of fatty acid synthase (FASN) are described. The compounds are shown to have antiviral (HCV replicon) activities that track with their biochemical activities. The most potent analogue (compound 19) also inhibits rat FASN and inhibits de novo palmitate synthesis in vitro (cell-based) as well as in vivo.

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.

Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.

The isoquinoline ring system is a reoccurring structural motif in alkaloids 1 and pharmaceuticals. 2 Consequently, the synthesis and functionalization of isoquinolines have attracted considerable attention from the synthetic community. 3 We previously reported a facile synthesis of 1,3,4-trisubstituted isoquinolines from commercially available 1,3-dichloroisoquinoline 1 ( Scheme 1 ). 4 A key step in the process is the direct lithiation of 1 at C4. The resulting lithium species 2 was trapped with a variety of electrophiles to produce 4-substituted-1,3-dichloroisoquinoline 3 , which was further elaborated to give1,3,4-trisubstituted isoquinoline 4 by exploiting the different reactivity of C1–Cl and C3–Cl bonds under Pd-catalysis.

A divergent synthesis of 1- and 5-substituted 3,9-diazaspiro[5.5]undecanes and undecan-2-ones is described, in which the key step is an efficient Michael addition of a lithium enolate to a tetrasubstituted olefin acceptor. A variety of substituents (butyl, phenyl, and propoxyl) were introduced at C-1(5) in this manner. In addition, an asymmetric synthesis of one member of this series was achieved using an Evans oxazolidinone chiral auxiliary reagent.

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

Let X be an infinite compact metrizable space having only a finite number of isolated points and Y be a non-degenerate dendrite with a distinguished end point v. For each continuous map ƒ : X → Y , we define the hypo-graph ↓vƒ = ∪ x∈X {x} × [v, ƒ (x)], where [v, ƒ (x)] is the unique arc from v to ƒ (x) in Y . Then we can regard ↓v C(X, Y ) = {↓vƒ | ƒ : X → Y is continuous} as the subspace of the hyperspace Cld(X × Y ) of nonempty closed sets in X × Y endowed with the Vietoris topology. Let be the closure of ↓v C(X, Y ) in Cld(X ×Y ). In this paper, we shall prove that the pair , ↓v C(X, Y )) is homeomorphic to (Q, c0), where Q = Iℕ is the Hilbert cube and c0 = {(xi )i∈ℕ ∈ Q | limi→∞xi = 0}.

Design, syntheses, and testing of new, fullerene-wheeled single molecular nanomachines, namely, nanocars and nanotrucks, are presented. These nanovehicles are composed of three basic components that include spherical fullerene wheels, freely rotating alkynyl axles, and a molecular chassis. The use of spherical wheels based on C60 and freely rotating axles based on alkynes permits directed nanoscale rolling of the molecular structure on gold surfaces. The rolling motion observed by STM resembles the same motion performed by macroscopic entities in which rolling occurs perpendicular to the axles. A new synthesis methodology, in situ ethynylation of fullerenes, was developed for the realization of the fullerene-wheeled molecular machines. Four generations of the fullerene-wheeled structures were developed, and the latest fourth generation nanocar, 3b, along with three-wheeled triangular compounds, 4a and 4b, provided definitive evidence for fullerene-based wheel-like rolling motion, not stick-slip or sliding translation. The studies here underscore the ability to control directionality of motion in molecular-sized nanostructures through precise molecular design and synthesis.

In this paper, realizing an infinite simplicial complex K in the linear space RK(0) naturally, we investigate the box topology on |K| inherited from RK(0) that is finer than the metric topology and coarser than the Whitehead (weak) topology.

Let X = (X, d) be a metric space. We use USC(X) to denote the family of all the upper semi-continuous maps from X to I = [0, 1]. For an arbitrary f ∈ USC(X), let ↓f = {(x, t) ∈ X × I|0 ≤ t ≤ f(x)} be the hypograph of f and Gf = {(x, f(x) ∈ X × I|f(x) > 0}. A upper semi-continuous map f is called strongly discontinuous if Gf is dense in ↓ f . Let SDC(X) be the set of all the strongly discontinuous maps. In this paper, we mainly proved that: If X is a locally compact, separable metric space with no isolated point, then (↓ USC(X), ↓ SDC(X)) ≈ (Q,s), where Q = [−1, 1]ω , s = (−1, 1)ω . ↓USC(X) and ↓SDC(X) denote the families of the hypographs of all upper semi-continuous maps and all strongly discontinuous maps equipped with Fell topology.

This paper reports the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. A ring-closing metathesis was utilized to form the 31-membered macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty of forming the C16-17 olefin in the late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment containing both the B- and C-ring subunits.

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for stereoselective assembly of the C-ring subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the C-ring subunit of bryostatins.

This article describes chemoselective and atom-economical methods for the stereoselective assembly of the A- and B-ring subunits of the bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition was developed and applied to the synthesis of the bryostatin B-ring. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin A-ring; and the A-ring was eventually furnished via an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of a northern bryostatin fragment containing both the A- and B-ring subunits.

This article describes chemoselective and atom-economic methods for the stereoselective assembly of the ring A and B subunits of bryostatins. A Ru-catalyzed tandem alkene-alkyne coupling/Michael addition reaction was developed and applied to the synthesis of bryostatin ring B. We explored an acetylide-mediated epoxide-opening/6-exo-dig cyclization route to access the bryostatin ring A, although ring A was eventually furnished through an acid-catalyzed tandem transketalization/ketalization sequence. In addition, a dinuclear zinc-catalyzed methyl vinyl ketone (MVK) aldol strategy was evaluated for the construction of the polyacetate moiety. Utilization of these methods ultimately led to the rapid assembly of the northern bryostatin fragment containing both the ring A and B subunits.

Herein, we report the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. Ring-closing metathesis was utilized to form the 31-membered ring macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty in forming the C16-C17 olefin at a late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment, containing both the ring B and C subunits.

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins.

The HIV/AIDS epidemic and the resultant therapeutic efforts have continued to evolve over the last several years. The continued challenges in vaccine development, the growing longevity of the patient population and the emergence of resistant strains to current highly active antiretroviral therapy necessitate the development of new, effective therapeutics which target novel mechanism of actions. CCR5, a member of the GPCR superfamily, plays a key role as a co-receptor during the HIV viral entry process. The utility of CCR5 antagonists in the clinical setting has been validated, culminating in the launch of maraviroc (Selzentry by Pfizer (New York, NY, USA) in 2007.This review covers patent applications for small-molecule CCR5 selective antagonists published between 2006 and 2008 and related literature, with a focus on the treatment of HIV infection.The reader will gain information on patent literature from 2006 to 2008 on CCR5 antagonists for the treatment of HIV infection.A variety of new chemotypes have emerged over this period. These efforts support the potential to develop the next generation of CCR5 antagonists for the treatment of HIV with improved potency, tolerability and convenience.

A facile and versatile approach to 1,3,4-trisubstituted isoquinoline derivatives from commercially available 1,3-dichloroisoquinoline is described.

A divergent synthesis of 1- and 5-substituted 3,9-diazaspiro[5.5]undecanes and undecan-2-ones is described, in which the key step is an efficient Michael addition of a lithium enolate to a tetrasubstituted olefin acceptor. A variety of substituents (butyl, phenyl, and propoxyl) were introduced at C-1(5) in this manner. In addition, an asymmetric synthesis of one member of this series was achieved using an Evans oxazolidinone chiral auxiliary reagent.

Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent.

Hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, are transcription factors that mediate cellular response to changes of oxygen supply. These proteins become stabilized under hypoxia and subsequently activate the expression of genes to facilitate cell survival and proliferation. HIF proteins are activated in many types of cancers due to the tumor hypoxic microenvironment and have been implicated in cancer initiation, progression and metastasis. The oncogenic role of HIF-2α is pertinent in clear cell renal carcinoma (ccRCC). In the majority of ccRCC tumors, the von Hippel-Lindau protein (VHL) that targets HIF-2α for degradation is inactivated, leading to the accumulation of HIF-2α and the activation of genes that drive kidney cancer tumorigenesis. We have identified small molecules that bind to the PAS-B domain of HIF-2α protein and block it's dimerization with ARNT (aryl hydrocarbon receptor nuclear translocator, HIF-1β), a prerequisite for its transcriptional activities. Specifically, we describe PT2385, a selective, orally active HIF-2α antagonist with potent anti-cancer activity in mouse models of ccRCC. PT2385 is currently under evaluation in Phase I clinical trials for the treatment of ccRCC. Citation Format: Eli M. Wallace, Zhaodan Cao, Tzuling Cheng, Robert Czerwinski, Darryl D. Dixon, Xinlin Du, Barry Goggin, Jonas Grina, Megan Halfmann, Guangzhou Han, Heli Huang, John A. Josey, Melissa A. Maddie, Sarah Olive, James Rizzi, Stephen T. Schlachter, Hui-Ling Tan, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang. PT2385: First-in-class HIF-2α antagonist for the treatment of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2015-DDT01-01

[reaction: see text] A Ru-catalyzed tandem alkyne-enone coupling/Michael addition reaction is reported. It provides an efficient, atom-economic entry to 4-methylene-2,6-cis-tetrahydropyrans from simple, readily available homopropargylic alcohols and beta,gamma-unsaturated enones in good yields. Further functionalization of the resultant vinylsilane leads to the synthesis of either geometrically defined trisubstituted alkene exocyclic to the 2,6-cis-dihydropyran.

Novel strategies are developed for an efficient formal synthesis of (-)-mycalamide A. The left-hand side (-)-7-benzoylpederic acid is synthesized from (2S,3S)-2,3-epoxybutane. The key features include a highly regioselective Ru-catalyzed alkene-alkyne coupling reaction and a novel way to control the challenging C(7) stereocenter. The right-hand side was synthesized from (R)-pantolactone. The complex trioxodecalin core is constructed with two Pd(0)-catalyzed O-pi-allyl cyclizations. The first one is chemoselective, while the second one is highly diastereoselective. Three additional steps would be required to complete a total synthesis of (-)-mycalamide A.

This review addresses key pharmacology and virology issues relevant in discovery and development of CCR5 antagonists as anti-HIV drugs, such as target validation, receptor internalization, allosterism, viral resistance and tropism. Recent progress in the discovery and development of CCR5 antagonists, SAR and clinical status are reviewed. Finally, modeling-based structure of CCR5 is discussed in the context of a small-molecule antagonism of the CCR5 receptor.

Wieslaw Kazmierski,* Neil Bifulco, Hanbiao Yang, Larry Boone, Felix DeAnda, Chris Watson and Terry Kenakin Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA Department of Virology, GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA Computational, Analytical and Structural Sciences, GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA Systems Research, GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA