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Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.

A newly reported strain of Vibrio cholerae, known as strain O139 Bengal, is the first instance of an encapsulated strain that has caused epidemic cholera. The O-antigenic capsule is the critical antigen for protective immunity. Since mapping of the antigenic epitopes will assist in the development of a protein conjugate vaccine based on the capsular polysaccharide, we have undertaken a study of the three-dimensional conformation of the polysaccharide. It contains six residues in the repeating subunit with the unusual feature of a 4,6 cyclic phosphate on a beta-galactopyranoside. A structural epitope composed of four of the residues is somewhat similar to the Lewis(b) blood group tetrasaccharide. Polysaccharide samples enriched in (13)C have been prepared by growth of the bacteria in (13)C-enriched medium. Multidimensional heteronuclear NMR and molecular modeling studies are reported, which show that the O139 tetrasaccharide adopts a compact and tightly folded conformation that is relatively rigid and similar to the Le(b) conformation. The cyclic phosphate on the beta-galactopyranoside residue is in contact with the colitose residue linked to the beta-GlcNAc.

Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic β-dicarbonyl. This design concept for leaving groups has not been previously reported. A structure-activity relationship has been developed and the concept extended to several types of alicyclic and heterocyclic β-dicarbonyl systems. This work led to the identification of a potent (K i * of 0.066 nM) and tissue stable (in vitro : blood t 1/2 = 160 min, liver t 1/2 > 240 min) benzisothiazolone HLE inhibitor, WIN 65936 (13b).

A series of 5-alkyl-1,7,8-trisubstituted-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was prepared and evaluated for in vitro and in vivo antibacterial activity. When compared to the 5-hydrogen analogues, the presence of the 5-methyl group enhanced in vitro potency for those compounds containing a cyclopropyl moiety at N 1 but decreased potency for those containing an ethyl group at N 1 . Replacing the 5-methyl with a 5-ethyl significantly reduced the efficacy. In general, the 5-methyl and 5-hydrogen analogues were equipotent in vivo. Several of the 5-methyl-1-cyclopropylquinolones displayed excellent in vitro and in vivo activity, warranting further development

A series of 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides was prepared from the substituted 1-phenyl-2-propanones proceeding through the 5-nitro[1,1'-biphenyl]-2-ols, the corresponding amino, and acetamido derivatives to the N-[5-[(alkylamino)methyl]-6-hydroxy[1,1'-biphenyl]-3-yl]acetamides and final condensation with 4,7-dichloroquinoline or the N-oxide. In a quantitative structure-activity relationship study first run on 28 and later expanded to 40 substituted phenyl analogues and their N omega-oxides, increasing antimalarial potency vs. Plasmodium berghei in mice was found to be correlated with decreasing size (sigma MR) and electron donation (sigma sigma) of the phenyl ring substituents. A significant correlation with N omega-oxidation could not be demonstrated. Initial high activity against P. berghei infections in mice led to expanded studies that demonstrated in addition excellent activity against resistant strains of parasite, activity in primate models, and pharmacokinetic properties apparently allowing protection against infection for extended periods of time even after oral administration. Such properties encourage the clinical trial of a member of this class in man.

N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines (1-15) and related N6-substituted 2,4,6-pteridinetriamines (16-20) were obtained by the condensation of 6-chloro-2,4-pteridinediamine with N-methylarylmethanamine and other selected secondary amines. The requisite N-methylarylmethanamines (21-32) were prepared by the hydrogenation over Pt/C of the corresponding arylcarboxaldehyde in the presence of methanamine. Several of the N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines exhibited exceptional suppressive antimalarial activity against a drug-sensitive line of Plasmodium berghei in mice. N6-Methyl-N6-(1-naphthalenylmethyl)-2,4,6-pteridinetriamine (9), the most active of these compounds, was also shown to be curative at 3.16 mg/kg in a single oral dose against P. cynomolgi in the rhesus monkey. This compound was also shown to be effective against a chloroquine-resistant line of P. berghei in the mouse but showed cross-resistance to a pyrimethamine-resistant strain. Most of the 2,4,6-pteridinetriamines showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.

An array of nonclassical thioquinazoline analogues (VIII) of methotrexate was prepared by cyclization of the requisite 2-amino-5-(arylthio)benzonitrile with chloroformamidine hydrochloride (28--79%). The aminonitrile precursors were obtained by SnCl2-HCl reduction (28--99%) of the corresponding 2-nitro-5-(arylthio)benzonitriles, which were synthesized by the condensation of the appropriate 5-chloro-2-nitrobenzonitriles with various arylthiols (36--83%). Many of the thioquinazolines (VIII) showed suppressive antimalarial activity comparable with or superior to chloroquine, cycloguanil, and pyrimethamine against drug-sensitive lines of Plasmodium berghei in mice and Plasmodium gallinaceum in chicks, and several displayed potent prophylactic activity with P. gallinaceum. Moreover, the thioquinazolines retained potent antimalarial effects against chloroquine-, cycloguanil-, pyrimethamine- and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys. The most active compound, namely, 2,4-diamino-6-[alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline, was designated for preclinical toxicological studies. Numerous substances exhibited in vitro activity against a broad spectrum of pathogenic bacteria at concentrations of less than 0.25 microgram/mL. The thioquinazolines also prove to be potent folate antagonists, causing 50% inhibition of Streptococcus faecalis R (ATCC 8043) at drug concentrations ranging from 0.2 to 2.0 ng/mL. Structure--activity relationships are discussed.

Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.

A series of 2,4-diamino-6-[(aralkyl and alicyclic)thio-, sulfinyl-, and sulfonyl]quinazolines was prepared via condensation of 5-chloro-2-nitrobenzonitrile or 5,6-dichloro-2-nitrobenzonitrile with the appropriate aralkyl or alicyclic thiopseudourea, reduction of the resulting 2-nitro-5-[(aralkyl or alicyclic)thio]benzonitrile with stannous chloride to the amine, and cyclization with chloroformamidine hydrochloride. Oxidation was effected with hydrogen peroxide or the bromine complex of 1,4-diazabicyclo[2.2.2]octane. These analogues when examined for suppressive activity against drug-sensitive lines of Plasmodium berghei in mice were not as active as 2,4-diamino-6-[3,4-dichlorobenzyl)amino]quinazoline (Ia).

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.

A series of N2(and N4)-aryl-N4(and N2)-[(dialkylamino)alkyl]-2,4-quinazolinediamines has been synthesized for antimalarial evaluation. Condensation of the appropriate 2,4-dichloroquinazoline (IV) with the requisite N,N-dialkylalkylenediamine afforded a series of 2-chloro-N-[(dialkylamino)alkyl]-4-quinazolinamines (V) which were condensed with the appropriate arylamine to provide the corresponding N2-aryl-N4-[(dialkylamino)alkyl]-2,4-quinazolinediamines (VI). Hydrolysis of 2,4-dichloroquinazoline to 2-chloro-4-quinazolinol was followed by condensation with the appropriate N,N-dialkylalkylenediamine to give an array of 2-[[(dialkylamino)alkyl]amino]-4-quinazolinols (IXa). Chlorination with phosphorus oxychloride and condensation with a requisite arylamine provided the N2-[(dialkylamino)alkyl]-N4-phenyl-2,4-quinazolinediamines (X). Antimalarial activity was general among the N2-aryl-N4-[(dialkylamino)alkyl]-2,4-quinazolinediamines (VI), while the reverse isomers were of lower activity. Phototoxic liability precluded clinical evaluation of a member of the series.

A series of 4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl]-6-alkylphenols and their N omega-oxides were synthesized by the condensation of 4,7-dichloroquinoline and 4,7-dichloroquinoline N omega-oxide with appropriately substituted 4-amino-2-[(diethylamino)methyl]-6-alkylphenol dihydrochlorides. The latter precursors were prepared in a six-step synthesis starting from available 2-alkylphenols. Several of the title compounds display potent antimalarial activity in mice.

Various 6-[[(aryl and aralkyl)amino]methyl]-2,4-pteridinediamines and their 8-oxides have been synthesized for antimalarial evaluation. Condensation of 3-amino-6-(bromomethyl)-2-pyrazinecarbonitrile 4-oxide (V) with the appropriately substituted amine afforded a series of 3-amino-6-[[(aryl and aralkyl)amino]methyl]-2-pyrazinecarbonitrile 4-oxides VI. Deoxygenation gave the corresponding pyrazines VII. Cyclization of VI and VII with guanidine then produced the desired 6-(aminomethyl)-2,4-pteridinediamine N-oxides VIII and teridinediamines IX, respectively. Formylation of 6-[[(3,4-dichlorophenyl)amino]methyl]-2,4-pteridinediamine gave N-[(2,4-diamino-6-pteridinyl)-methyl]-N-(3,4-dichlorophenyl)formamide. The N-oxides VIII did not exhibit significant activity against Plasmodium berghei infections in mice. Activity among the 2,4-pteridinediamines IX was generally poor with the exception of the 3,4,5-trimethoxyphenyl and 1-naphthalenyl analogues which showed strong suppressive activity at doses ranging from 80 to 640 mg/kg. Furthermore, several of the 2,4-pteridinediamines exhibited potent prophylactic activity against Plasmodium gallinaceum infections in the chick and also showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.

Involves a Beer's Law plot calibration, a elutropic series, and microvolumetric techniques.