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Angiogenesis, the formation of new blood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption of these events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR1TK inhibitor, were evaluated for their anti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285 inhibited PDGFR-beta-, EGFR-, and FGFR1TKs and c-src TK by 50% (IC50) at concentrations between 7-85 nM. PD173074 displayed selective inhibitory activity towards FGFR1TK at 26 nM. PD173074 demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelial cells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10 nM) inhibited the formation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration (p.o.) of either PD166285 (1-25 mg/kg) or PD173074 (25-100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor, significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5-10 mg/kg) or PD173074 (30-60 mg/kg) following PDT compared with PDT alone (p

Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

Syntheses and structure-activity relationships for a series of substituted tetrahydroisoquinoline-3-carboxylic acid derivatives with AT2-specific angiotensin II receptor binding inhibitory activity are reported.

A synthesis of 6-amino-7-cyclohexyl-3,5-heptanediol 1 (CDH) and related amino 1,3-diols involving a nucleophilic ring opening of N-acyl activated lactams is described. Stereochemical proof of the 1,3-diol moiety is also presented.

New derivatives of the naturally occurring amino acid 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (spinacine) are reported. These include amide, ester, 5-alkyl and acyl, and regiospecific N im -alkyl and aralkyl derivatives. Synthesis via the Pictet-Spengler reaction of N im -substituted histidines is described. Cyclic hydantoin derivatives of spinacines are included

While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.

Raised blood pressure in the elderly is not a normal consequences of aging, but is a major risk factor for cardiovascular disease. Cardiac and cerebrovascular disease account for50% of deaths among people aged65 years. Because the percentage of elderly people in most populations is rising, blood pressure control in this group is becoming increasingly important. Several large intervention studies in the elderly have demonstrated that antihypertensive medication reduces cardiovascular morbidity and mortality. In addition, the absolute benefits of blood pressure reduction are higher in elderly compared with younger patients. ACE inhibitors are effective and well tolerated in the treatment of hypertension in the elderly. Their success led to interest in alternative ways of blocking the renin angiotensin system, and the subsequent development of angiotensin II (AII) receptor antagonists. Losartan was the first drug in this class to become commercially available. Since then, valsartan has been launched in some markets and others are likely to be launched in the near future. Losartan is effective in the treatment of essential hypertension and has a low incidence of adverse effects. First-dose hypotension is very uncommon and, at the present time, cough does not appear to be an adverse effect of these drugs, although long term tolerability studies are needed to confirm this. Angioedema, a rare but life-threatening adverse effect of ACE inhibitors, has also been associated with losartan. Current data suggest that All receptor antagonists are effective in elderly hypertensive patients, although further data are needed to confirm these findings. At present, All receptor antagonists are likely to be used in hypertensive patients who are intolerant of ACE inhibitors, although this may change with the availability of long term tolerability and clinical outcomes data.

To understand the differences in the binding specificities within the aspartic proteinase family of enzymes, we have carried out studies to determine the inhibition constants of a set of related compounds with various members of the human enzyme family. The inhibition constants (Ki values) were determined by competitive inhibition of the hydrolysis of chromogenic octapeptide substrates in the pH range of 3-5. For comparison, inhibition of monkey renin was studied by RIA at pH 6.0. All inhibitors were based on the general structure 4-(morpholinylsulfonyl)-L-Phe-P2-(cyclohexyl)Ala psi[isostere]-P1'-P2'. The isosteric replacements of the scissile peptide bond included difluorohydroxyethylene, 1,2-diols, 1,3-diols, and difluoroketones. Side chain substituents in P2 include hydrogen, allyl, ethylthio, (methoxycarbonyl)methyl, N-methylthiouridobutyl, imidazolylmethyl, and 4-amino-2-thiazolylmethyl. Our measurements have identified potent and selective inhibitors which are useful in evaluating the differences in the specificities among selected enzymes of this family.

Aspartic Proteinases are produced in the human body by a variety of cells. Some of these proteins, for example, pepsin, gastricsin and renin are secreted and exert their effects in the extracellular spaces. Cathepsin D and cathepsin E, on the other hand, are intracellular enzymes.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

A novel synthesis of 3-(hydroxymethyl)chromones from o-hydroxy-ω-(methylsulfinyl)acetophenones has been developed. These have been utilized in the synthesis of 3-formyl, 3-cyano, 3-carboxy, 3-carboxamido, 3-chloromethyl, 3-aminomethyl and 3-methoxymethylchromones.

The thermal rearrangement of antifungal antibiotic 1, isolated from Polyangium cellulosum var. fulvum, to cycloheptadiene derivative 2 is described.

A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.

A number of gamma- and delta-lactam derivatives were synthesized and their in vitro angiotensin-converting enzyme (ACE) inhibitory activities were compared. The structures of these compounds were designed to include many of the important features of captopril. The synthesis involved the preparation of a variety of novel 3-methylene-2-pyrrolidinones (3-5 and 16) and 3-methylene-2-piperidinones (3a-5a, 10-12, and 17). The key intermediate 3-methylenelactams 3 and 3a were obtained from 3-(hydroxymethyl)lactams 2 and 2a by a direct dehydration with dicyclohexylcarbodiimide using cuprous iodide as a catalyst. Introduction of the sulfhydryl group was accomplished by a Michael addition of these alpha, beta-unsaturated lactams. The compound with the highest in vitro activity was 3-(mercaptomethyl)-2-oxo-1-piperidineacetic acid (7a). The activity of the 7a both in vitro and in vivo (dog) was shown to be less than that of captopril by a factor of about 100.