Identification and SAR for a selective, nonpeptidyl thrombin inhibitor.

A novel, nonpeptidyl thrombin inhibitor, L-636,619 (1), was identified via topological similarity searching over the Merck Corporate Sample Database. X-ray crystallographic studies determined the geometry for ligand binding to the enzyme. Chemical modification of the P1 and P3 segments of the ligand resulted in enhanced potency and improvement in the chemical stability of the lead. Analog 9 proved to be the most interesting lead from this structurally novel series.

Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors.

The 3-dimensional structure of human carbonic anhydrase II (HCAII; EC 4.2.1.1) complexed with 3 structurally related inhibitors, 1a, 1b, and 1c, has been determined by X-ray crystallographic methods. The 3 inhibitors (1a = C8H12N2O4S3) vary only in the length of the substituent on the 4-amino group: 1a, proton; 1b, methyl; and 1c, ethyl. The binding constants (Ki's) for 1a, 1b, and 1c to HCAII are 1.52, 1.88, and 0.37 nM, respectively. These structures were solved to learn if any structural cause could be found for the difference in binding. In the complex with inhibitors 1a and 1b, electron density can be observed for His-64 and a bound water molecule in the native positions. When inhibitor 1c is bound, the side chain attached to the 4-amino group is positioned so that His-64 can only occupy the alternate position and the bound water is absent. While a variety of factors contribute to the observed binding constants, the major reason 1c binds tighter to HCAII than does 1a or 1b appears to be entropy: the increase in entropy when the bound water molecule is released contributes to the increase in binding and overcomes the small penalty for putting the His-64 side chain in a higher energy state.

Topically active carbonic anhydrase inhibitors. 2. Benzo[b]thiophenesulfonamide derivatives with ocular hypotensive activity.

Derivatives of benzo[b]thiophene-2-sulfonamide were prepared to investigate their potential utility as topically active inhibitors of ocular carbonic anhydrase. Such an agent would be useful in the treatment of glaucoma. Among the compounds described are 6-hydroxybenzo[b]thiophene-2-sulfonamide (16) and its acetate ester (23), which are among the most potent ocular hypotensive agents in this class, as assessed in the alpha-chymotrypsinized rabbit. These compounds were selected for clinical evaluation.

Thienothiopyran-2-sulfonamides: a novel class of water-soluble carbonic anhydrase inhibitors.

An attempt to develop a water-soluble carbonic anhydrase inhibitor focused on exploring structure-activity relationships in the thienothiopyransulfonamide class. The strategy to influence water solubility while retaining carbonic anhydrase activity involved the introduction of a hydroxyl moiety and adjusting the oxidation state of the sulfur on the thiopyran portion of the molecule. Compounds 4 and 17 best fit the criteria of aqueous solubility and inhibitory potency vs. human carbonic anhydrase II and are candidates for evaluation as topically effective antiglaucoma agents.

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy]phenyl]imidazole class. 2.

An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.

A deuterium isotope effect on the inhibition of gastric secretion by N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea. Synthesis of metabolites.

The use of isotopic substitution to retard the oxidative metabolism of the gastric antisecretory agent N,N-dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (1) and improve its antisecretory potency was examined. The pyridine ring methyl hydrogens of 1 were replaced with either deuterium or fluorine. The hexadeuterated analogue (12) was found to be approximately 2.1 times more potent than the protio form (1) as an inhibitor of gastric acid secretion stimulated by gastrin tetrapeptide. The hexafluoro analogue (11) was 0.4 times as potent as 1. A useful pyridine ring synthesis was developed to prepare the metabolites of 1, 10a (4-hydroxymethyl) and 10b (6-hydroxymethyl), and the hexafluoro analogue 11. These syntheses involved the condensation of 1,3-diketones with an appropriately N-substituted amidinoacetate.

Inhibitors of gastric acid secretion: antisecretory 2-pyridylurea derivatives.

A series of aminoalkyl-substituted pyridylureas has been prepared and evaluated as inhibitors of gastric acid secretion. N,N-Dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (8g) was the most potent example of the class. Comparison of this compound with cimetidine showed it to be equipotent in dogs stimulated with gastrin tetrapeptide but approximately half as potent in dogs stimulated with histamine. Inhibition of secretion does not appear to result from antagonism of the histamine H2 receptor, since the compounds show only weak inhibition of the H2 receptor in vitro.

Conformational requirements for histamine H2-receptor inhibitors: a structure-activity study of phenylene analogues related to cimetidine and tiotidine.

Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine 1,1-diamino-2-nitroethene or 3,4-diamino-1,2,5-thiadiazole 1-oxide, each 3 3-(2-guanidino-4-thiazolyl)phenyl analogue was ca. 8 and 90 times more potent intravenously than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. It was concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H2 receptor.

2-Mercaptoacetamidines as gastric antisecretory agents.

A series of N-substituted 2-mercaptoacetamidines was synthesized and evaluated for gastric antisecretory activity in dogs stimulated with gastrin tetrapeptide. The most potent analogues showed 80--95% inhibition of acid secretion after an oral dose of 8 mg/kg. Thus, these compounds represent a new structural type having significant antisecretory activity. Disulfides had essentially the same antisecretory potency as the corresponding mercaptoacetamidines, indicating a metabolic interconversion. Alkylation of the mercapto group decreased potency. Higher carboxamidine homologues such as 2- and 3-mercaptopropionamidines had very low activity. Hydroxyacetamidines and mercaptoacetamides also had low potency. Side effects observed with this series of compounds included emesis, tachycardia, and gastric bleeding.