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The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.

Important progress towards the total syntheses of the title compounds, potent inhibitors of squalene synthase and farnesyl transferase, has been accomplished by the construction of the highly functionalized compound 1.

Ein entscheidender Schritt auf dem Weg zur Totalsynthese der Titelverbindungen, die die Squalen-Synthase und Farnesyl-Transferase inhibieren, gelang durch den Aufbau der hochfunktionalisierten zentralen Ausgangsverbindung 1.

The first total syntheses of the cytotoxic marine natural product, aplysiapyranoid C, 1c, are reported. The Wittig reaction of 4-methyl-3-pentenyltriphenylphosphorane with the THP ether of hydroxyacetone gave in 88% yield the Z-alkene 4 which was hydrolyzed to the alcohol 5 in 72% yield. Sharpless asymmetric epoxidation of 5 afforded the epoxy alcohol 6 in 91% yield and 81% ee. Opening of the epoxide of 6 with ammonium chloride in DMSO gave in 76% yield the chloro diol 7 which was converted to the primary TBS ether 8 in 95% yield. Opening of the epoxy alcohol 6 with HCl and Ti(OiPr)4 afforded the desired chloro diol 7 as the minor product along with the rearranged chloromethyl diol 9. This compound is presumably formed by opening of the protonated epoxide to give a butenyl cation which rearranges to the cyclopropylcarbinyl cation and is then trapped by chloride ion at the unsubstituted cyclopropyl carbon, regenerating the alkene. Cyclization of the TBS ether 8 with tetrabromocyclohexadienone (TBCO) afford...

A novel method for the synthesis of a series of silyl ethers of 3-(silyloxy)tetrahydrofuran-2-methanols bearing substituents at all four carbon atoms of the ring has been developed. The process inv...

Several intramolecular Prins double cyclizations are reported. The 2-alkyl 5-hepten-1,2-diols and their analogues, 9−11, were prepared and oxidized to the aldehydes 6−8 under Swern conditions. Treatment of these α-hydroxy aldehydes with TBSOTf and a hindered base gave the products of an intramolecular Prins double cyclization, namely the 7-(silyloxy)-2-oxabicyclo[2.2.1]heptanes, 17−19, in 84−92% yield. These compounds were formed as single diastereomers with only the anti silyl ethers being obtained. The cyclizations occur when five-membered rings are being formed and when the initially formed cation is highly stabilized. Other substrates do not cyclize, e.g., when the α-hydroxy aldehydes 20−22, prepared from 26−28, are treated under similar conditions, none of the corresponding cyclization products, 23−25, were obtained.

The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.

Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.

Herein is described an efficient total synthesis of aplysiapyranoid A, 1a, in which the key step is the diastereoselective bromoetherification of the hydroxy alkene 14 to give mainly the desired isomer 1a.

Important progress towards the total syntheses of the title compounds, potent inhibitors of squalene synthase and farnesyl transferase, has been accomplished by the construction of the highly functionalized compound 1.

We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.

Das quartare Stereozentrum an C7 einer Vorstufe der Titelverbindungen konnte durch Addition des von Trost beschriebenen Ylids an 1 aufgebaut werden. Dies und eine Photooxidation, die die Maleinsaureanhydrid-Einheit liefert, sind zwei weitere wichtige Schritte fur die Totalsynthese der beiden Verbindungen.

The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.

A low molecular weight endogenous substance believed to be responsible for extracellular fluid homeostasis in mammals has been sought for many years. Our goal is to isolate and structurally characterize this putative {open_quotes}natriuretic hormone{close_quotes}. We have developed an assay using the conscious rat to measure prolonged natriuresis, the activity originally described for this putative substance. Using this assay we have identified a number of natriuretic compounds isolated from human uremic urine. The collected urine is processed by ultrafiltration ({le} 3 kDa), gel filtration chromatography (G-25) and extraction with isopropanol and diethyl ether. The organic soluble material is then subjected to sequential high-performance liquid chromatography. We report here the initial characterization of two pure isolates (LLU-{alpha} and LLU-{gamma}) obtained by this method, and the structural elucidation of a third pure compound, LLU-{beta}{sub 1}, a natriuretic and previously unreported metabolite of the drug diltiazem. 33 refs., 7 figs., 4 tabs.