Cell adhesion antagonists: synthesis and evaluation of a novel series of phenylalanine based inhibitors.

Several phenylalanine based inhibitors were synthesized as antagonists of the leukocyte cell adhesion process that is mediated through the interactions of the mucosal addressin cell adhesion molecule (MAdCAM) and the integrin alpha4beta7. Analogues 20, 21, 22 and 24 displayed inhibition of adhesion in a cell based assay in the low micromolar range.

Novel modified tripeptide inhibitors of alpha 4 beta 7 mediated lymphoid cell adhesion to MAdCAM-1.

MAdCAM-1 specifically binds the lymphocyte integrin alpha 4 beta 7 and participates in the homing of leukocytes to intestinal mucosal sites. The LDT sequence located on the CD loop of MAdCAM-1 is an important binding site for MAdCAM-1/alpha 4 beta 7 interactions. N-Terminus acylation of the LDT motif and modification of the C-terminus carboxamide with amines led to low micromolar MAdCAM-1 inhibitors.

Design and discovery of RWJ 22108--a novel bronchoselective calcium channel blocker.

A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.

Phosphatase inhibitors--III. Benzylaminophosphonic acids as potent inhibitors of human prostatic acid phosphatase.

Further investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has led to the highly potent series of alpha-aminobenzylphosphonic acids. The alpha-benzylaminobenzylphosphonic acid, with an IC50 = 4 nM, exhibited a 3500-fold improvement in potency over the carbon analogue, alpha-phenylethyl. The enhanced potency may be due to a combination of four favorable interactions including those with the phosphate binding region, the presence the hydrophobic moieties of the benzylamino and phenylphosphonic acid, and a rigid conformer produced by an internal salt bridge between the phosphonate and the alpha-amino group. Replacement of the phosphonic acid moiety with a phosphinic or carboxylic acid as well as deletion of the benzyl substitution of the alpha-amino group led to great reductions in potency.

Synthesis and 5-lipoxygenase inhibitory activities of some novel 2-substituted 5-benzofuran hydroxamic acids.

A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

Novel bishydroxamic acids as 5-lipoxygenase inhibitors.

Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.

A comparison of progestin and androgen receptor binding using the CoMFA technique.

A series of 48 steroids has been studied with the SYBYL QSAR module using Relative Binding Affinities (RBAs) to progesterone and androgen receptors obtained from the literature. Models for the progesterone and androgen data were developed. Both models show regions where sterics and electrostatics correlate to binding affinity but are different for androgen and progesterone which suggests differences possibly important for receptor selectivity. The progesterone model is more predictive than the androgen (predictive r2 of 0.725 vs. 0.545 for progesterone and androgen, respectively).

3-(aminoalkyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridin-5-ones as potential anticholinergic bronchodilators.

A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridin-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine beta-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon alpha to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.

Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones.

The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic.

8-Amino-9-substituted guanines: potent purine nucleoside phosphorylase (PNP) inhibitors.

A series of 8-amino-9-substituted guanines was synthesized and their activity evaluated against human purine nucleoside phosphorylase (PNP). All compounds were found to be potent inhibitors of human PNP (IC50s: 0.17-126 microM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 microM) of the PNP substrate, 2'-deoxyguanosine (GdR). The most potent of these analogs, 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (8-amino-9-(2-thienylmethyl)guanine; PD 119,229) has an IC50 of 0.17 microM (Ki = 0.067 microM), significantly more potent than the known standard, 8-aminoguanosine (IC50 = 1.40 microM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.

Antipsoriatic drugs as inhibitors of soybean lipoxygenase. A possible mode of action.

Eight known antipsoriatic drugs of diverse structures were tested on the basis of their structural similarity with arachidonic acid and known inhibitors of lipoxygenase. A correlation was observed between their antipsoriatic activity and lipoxygenase inhibition suggesting that a common underlying mechanism of action might be involved.

Soybean lipoxygenase inhibition by nonsteroidal antiinflammatory drugs.

Eighteen known nonsteroidal antiinflammatory drugs (NSAID) were tested for their action against soybean lipoxygenase (E.C.1.13.11.12) using linoleic acid as substrate. It was found that the best inhibitors of lipoxygenase were naproxen, BW 755C, indomethacin and isoxicam. Drugs with intermediate potency were meclofenamic acid, phenylbutazone and benoxaprofen. Other drugs such as ibuprofen and zomepirac were only weakly active in the test.

Alkaline phosphatase inhibition by a series of pyrido[2,1-b]quinazolines: A possible relationship with cromolyn-like antiallergy activity.

Several known antiallergic agents, including cromolyn sodium and a series of pyrido[2,1-b]quinazolines, inhibit human alkaline phosphatase (ALP), a membranal enzyme associated with calcium uptake in certain tissues. A comparison of ALP and rat passive cutaneous anaphylaxis (PCA) inhibition indicates that PCA inhibition may be associated with drug-ALP interaction, since ALP inhibition potency parallels PCA inhibitory activity. The unpredictability of the PCA test toward clinical efficacy could in part be related to the uncompetitive nature of these inhibitors. The results also suggest that alkaline phosphatase may be a component of membranal calcium channels.

Potential histamine H2-receptor blockers. 3- and 2-indole derivatives as immobile analogues of tautomeric forms of cimetidine.

At physiological pH, cimetidine (1a) and its analogues burimamide (1b) and metiamide (1c) exist mainly as an equilibrium mixture of tautomers. A high concentration of tautomer 2 is associated with increased H2-receptor interaction. 3-Indole derivatives (5c-f) and 2-indole derivatives (6c-f) were synthesized and tested as immobile analogues of tautomers 2 and 3, respectively. Weak competitive H2 antagonism was found in N'-cyano-N-[2-[(1H-indol-3-ylmethyl)thio]ethyl]carbamidothioic acid methyl ester (5e) and N-[2-[(1H-indol-2-ylmethyl)thio]-ethyl]-N'-methylthiourea (6c).

Antiallergy activity of 10-oxo-10-H-pyridazino[6,1-b]quinazoline-2-carboxylic acids.

A series of substituted 10-oxo-10H-pyridazino[6,1-b]quinazoline-2-carboxylic acids was prepared and evaluated as antiallergy agents. The 8-chloro and unsubstituted analogues were more potent that cromolyn sodium and doxantrazole intravenously in the rat PCA test. None of the analogues possessed significant oral activity.

Antiallergy activity of substituted 11-oxo-11 H-pyrido[2,1-b]quinazoline-8-carboxylic acids.

A series of substituted 11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated as antiallergy agents. Several analogues were orally active. 2-Methyl-11-oxo-11H-pyrido[2,1-b]quinoazoline-8-carboxylic acid (6) was superior to cromolyn sodium and doxantrazole orally and intravenously in the rat PCA test and a rat allergic bronchospasm model.

11-Oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, an orally active antiallergy agent.

A new series of 11-oxo-11H-pyrido[2,1-b]quinazolinecarboxylic acids and related analogues has been synthesized and evaluated as potential antiallergy agents. In the rat PCA test, 11-oxo-11H-pyrido[2,1--b]quinazoline-8-carboxylic acid is orally active and more potent than cromolyn sodium or doxantrazole intravenously.