The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras

Inhibitors of farnesyl protein transferase

Pharmacophore modeling and 3D database searching are now recognized as integral components of lead discovery and lead optimization, and the continuing need for improved pharmacophore-based tools has driven the development of PHASE. By employing a novel, tree-based partitioning algorithm, PHASE exhaustively identifies spatial arrangements of functional groups that are common and essential to the biologic activity of a set of high affinity ligands. These pharmacophore hypotheses are validated in a number of ways, including their ability to: (i) rationalize the binding affinities of a training set of molecules of varying activity, (ii) successfully predict the affinities of a test set of molecules, and (iii) selectively retrieve known actives from a database of drug-like molecules. In addition, PHASE uniquely offers the ability to distinguish multiple binding modes through a bi-directional clustering approach applied to bit string representations of the ligand/hypothesis space.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1747-0285.2006.00384.x

PHASE: A Novel Approach to Pharmacophore Modeling and 3D Database Searching

This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

/pdf/chromone-a-valid-scaffold-in-medicinal-chemistry-4qd4v5m5z2.pdf

Chromone: A Valid Scaffold in Medicinal Chemistry

Although phenolic compounds are present in both the plant and animal worlds, most of them are of plant origin.1 This heterogeneous group of natural compounds is still, in many textbooks, described as “secondary metabolites”, which suggests their less important role in cellular physiology and biochemistry. It includes both simple phenols and polyphenols as well as their derivatives. In general, the term “phenol” can be defined chemically as a substance that possesses an aromatic ring bearing a hydroxyl substituent and functional derivatives. The natural plant phenols arise biogenetically from two main pathways: the shikimate pathway, which directly provides phenylpropanoids such as the hydroxycinnamic acids and coumarins, and the polyketide (acetate) pathway, which can produce simple phenols and also lead to quinones. The flavonoids, by far the largest group of phenolics, are derived by combination of these two pathways. Among plant single-ring phenolics the group of various compounds that has recently shown growth is the derivatives described as phenolic lipids or long-chain phenols.2 They are amphiphilic in nature due to the non-isoprenoid side chains attached to the hydroxybenzene ring and are believed to be also derived from the polyketide (acetate) pathway, as, for example, 6-pentadecylsalicylic acid. Non-isoprenoid phenolic lipids are relatively uncommon and can be considered for simplicity as fatty acids, with the carboxyl group replaced by the hydroxybenzene ring. Therefore, they are derivatives of monoand dihydroxyphenols, namely, catechol, resorcinol, and hydroquinone. The biogenetic pathway of these compounds, described in textbooks and recent reviews,2-5 is based on incomplete experimental data supplemented with chemical considerations. The biosynthetic aspects of resorcinolic lipids Volume 99, Number 1 January 1999

http://www.halsanet.com/pdf/340516159.pdf

Resorcinolic Lipids, the Natural Non-isoprenoid Phenolic Amphiphiles and Their Biological Activity.

Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals

A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test. These compounds are active when administered orally in rats and of possible value for the treatment of asthma.

Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances.

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines.

of the Disclosure Novel trisubstituted piperazine compounds of the formula (I): (I) wherein A is an optionally substituted phenyl group, an optionally substituted condensed polycyclic hydrocarbon group, an optionally substituted hetero-cyclic group or a styryl group of the formula: Ar - CR4 = CR5 - wherein Ar is an optionally substituted phenyl group, and R4 and R5 are independently hydrogen or a lower alkyl group, X is methylene group, carbonyl group or thiocarbonyl group, G is a group of the formula: ?CH2?nZ-R6 wherein n is an integer of 0 to 2, Z is a chemical bond, O, S, SO, SO2, CO, COO, CONR7 or NR7 (wherein R7 is hydrogen, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group or a lower alkoxycarbonyl group), and R6 is hydrogen a lower alkyl group, a lower haloalkyl group or a lower alkenyl group, provided that, when n is O and Z is chemical bond, R6 is not hydrogen or lower alkyl, and R1, R2 and R3 are independently a lower alkyl group, and salts thereof, are useful as a platelet activating factor antagonist.

Trisubstituted piperazine compounds, their production and use

Based on the lead tetrapeptide RGDF, two possible non-peptide glycoprotein (GP) IIb-IIIa antagonists possessing an (S)-2-oxopiperazine-3-acetic acid moiety as a scaffold incorporating the indispensable Asp fragment were prepared, and (S)-4-[[trans-[4-(guanidinomethyl)cyclohexyl]carbonyl]glycyl]-2-oxopiperazine-1,3-diacetic acid, 1a, was identified as a potential lead. A series of 3-substituted 2-oxopiperazine-1-acetic acids bearing the Arg-Gly equivalent at the 4-position were prepared and evaluated for their ability to prevent platelet aggregation and for their binding affinity for the GP IIb-IIIa receptor purified from human HEL cells. (S)-4-[(4-Amidinobenzoyl)glycyl]-3-[(methoxycarbonyl)methyl]-2-oxopiperazine-1-acetic acid, 9 (TAK-029), inhibited in vitro human platelet aggregation with an IC50 value of 0.03 μM and GP IIb-IIIa−fibrinogen binding with an IC50 value of 0.49 nM. The [4-(2-aminoethyl)benzoyl]glycyl derivative 26 showed activity comparable to that of 9 (IC50 = 0.093 μM, guinea pig platelet...

Novel Non-Peptide Fibrinogen Receptor Antagonists. 1. Synthesis and Glycoprotein IIb-IIIa Antagonistic Activities of 1,3,4-Trisubstituted 2-Oxopiperazine Derivatives Incorporating Side-Chain Functions of the RGDF Peptide

A seires of (R)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acids (8) and (S)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzoxazepine-5-acetic acids (9) having an (S)-1-carboxy-ω-(4-piperidyl)alkyl group on the amino group at the 3-position was prepared as part of a search for long-acting inhibitors of the angiotensin converting enzyme (ACE). The length (n) of the carbon chain in the piperidylalkyl moiety was varied from two six in order to determine the optimal structure. The most prolonged activity in vivo was observed with (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid (8c : CV-5975) on i.v. and p.o. administrations.

https://www.jstage.jst.go.jp/article/cpb1958/34/3/34_3_1128/_pdf

Hirosada Sugihara

Papers

Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances.

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines.

Trisubstituted piperazine compounds, their production and use

Novel Non-Peptide Fibrinogen Receptor Antagonists. 1. Synthesis and Glycoprotein IIb-IIIa Antagonistic Activities of 1,3,4-Trisubstituted 2-Oxopiperazine Derivatives Incorporating Side-Chain Functions of the RGDF Peptide

Synthesis and Angiotensin converting Enzyme Inhibitory Activity of 1, 5-Benzothiazepine and 1, 5-Benzoxazepine Derivatives. II