Synthesis and antihypertensive activity of some thienylethanolamines.

Synthesis of a series of thienylethanolamines having varying substituents on the thiophene ring and on the nitrogen atom is described using the general procedure reported earlier. In the determination of their pharmacological profile, some of the derivatives showed marked antihypertensive activity in the spontaneously hypertensive rat model. Tests are also reported which demonstrated that some of these derivatives antagonized alpha- and/or beta-adrenoreceptor activities. The ability of this class of compounds to inhibit catecholamine-induced release of free fatty acids by adipose tissue was demonstrated. Structure-activity relationships in different tests were also determined.

Troponoids. 3. Synthesis and antiallergy activity of N-troponyloxamic acid esters.

A number of oxamic acid derivatives of tropones and tropolones were synthesized and their antianaphylactic activity was determined in passive paw anaphylaxis (PPA). Several of these esters possessed oral activity. A comparison of the effect on the biological activity of the esters and the corresponding acid and its salt is reported. The experiments suggesting a relationship between the activity and the bioavailability of the ester 19 are also described. A study of the fate of ester 19 in serum on oral or intravenous administration to rats and dogs is reported. In vitro results of the effect of the compounds 19, 45, and 45a on the activity of the guinea pig lung and beef heart phosphodiesterase are presented. The various factors that may contribute to the antiallergy activity of compounds of this series are discussed.

Synthesis and selective class III antiarrhythmic activity of novel N-heteroaralkyl-substituted 1-(aryloxy)-2-propanolamine and related propylamine derivatives.

The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None of these compounds showed any class I activity. On the basis of the in vitro data, structure-activity relationships for the series are discussed. Two compounds, N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino] propoxy]phenyl]methanesulfonamide (12,WAY-123,223) and N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl] amino]methyl]-6-quinolinyl]-methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo. Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv). The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen. Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).

Antihyperglycemic activity of novel substituted 3H-1,2,3,5-oxathiadiazole 2-oxides.

A series of substituted 3H-1,2,3,5-oxathiadiazole-2-oxides (6) was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. The oxathiadiazoles 6 were synthesized by a two-step sequence: treatment of a substituted acetonitrile (4) with hydroxylamine to give the corresponding amidoxime (5) and cyclization with thionyl chloride to yield 6. In terms of potency, the 2-naphthalenylmethyl group (as in compound 3) was found to be the optimal substituent in this series. Compound 3 was approximately 5 times more potent than ciglitazone (1).

Antihyperglycemic activity of novel naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides.

A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. Substitution at the 1-, 5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4-[(5-Chloronaphthalen-2-yl)methyl]-3H-1,2,3,5-oxathiadiazole++ + 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.

Metabolites of the angiotensin II antagonist tasosartan: the importance of a second acidic group.

Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.

Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides.

The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.

Prostaglandins II--an improved synthesis and structural proof of (plus or minus)-11-deoxyprostaglandin F-1-beta.

PIP: Reported here is an improved synthesis and physicochemical evidences for the stereochemical assignments of (+/-)-11-deoxyprostaglandin F1beta. The stereochemistry of asymmetric centers are established (configurations published) and confirmed by ozonolysis of the diacetoxy methyl ester XII, followed by decomposition of the oxonide with 30% hydrogen peroxide in acetic acid at 50 degrees over 40 hours: this gave a crude mixture. Esterification of the acidic product with diazomethane followed by chromatography yielded an acetoxy diester identical in all respects with that obtained from alcohol VII (pictured in text). This evidence assigns conclusively the stereochemistry at carbon atoms C-8, C-9, and C-12. In the compound under investigation, the mode of genesis of asymmetric center at C-15 is beyond stereochemical control and a mixture of stereoisomers is expected.^ieng

Prostaglandins. IV. Total syntheses of dl-11-deoxy PGE 1 and 13,14-dihydro derivatives of 11-deoxy PGE 1 , PGF 1 , and PGF 1 .

PIP: A photoannelation reaction between 2 alpha, beta-unsaturated ketones is described. The photoadduct was isolated and characterized by spectral analysis and was transformed into methoxy and acetoxy derivatives. Some mechanistic implications of photoannelation and the finding of a rearrangement product are discussed. Transformations of diketone to other prostanoic acid derivatives are also described. Structural formulas are depicted in a stepwise manner.^ieng

A comparison of the bronchodilator activity of (+/-) 11-deoxy prostaglandin E1 with its 15-methyl analogue, (doxaprost).

The bronchodilator activity of (+/-) 11-deoxy prostaglandin E1 was compared to the activity of its (+/-) 15-methyl analogue, (doxaprost). Both compounds inhibited histamine-induced bronchoconstriction in the anesthetized guinea pig where changes in tracheal pressure were measured. Doxaprost was 73 and 32 times more potent that (+/-) 11-deoxy PGE1 by the aerosol and i.v. routes, respectively. Doxaprost also demonstrated a longer duration of effect. Both compounds decreased pulmonary resistance in the 5HT tonal cat. There was no difference in the potency of the two compounds. However, doxaprost had a longer duration of effect. Both compounds caused a fall in mean arterial blood pressure after i.v. administration in the guinea pig but not after aerosol administration in the guinea pig and cat. Both compounds caused relaxation of the isolated guinea pig tracheal strip when tone was induced with carbachol. There was no difference in the potency of the two compounds. The increased activity in vivo but not in vitro of the 15-methyl analogue doxaprost is consistent with a lack of enzyme inactivation.

The design, synthesis and physical chemical properties of novel human vasopressin V2-receptor antagonists optimized for parenteral delivery.

Ionizable groups were introduced onto the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine scaffold of the vasopressin V2-antagonist WAY-VPA-985 in the search for molecules optimized for parenteral formulation. The synthesis and structure activity relationships (SAR) are presented together with solubility data in a model parenteral system. The amine, WAY-140288 (4f), was chosen for further development. p6