ABSTRACT
4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC50) was 13.4 microM], it had no effect on the stimulated release of [3H]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC50 was 9.4 microM) but showed no activity as a release. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'-dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.
Subject(s)
Acetylcholine/metabolism , Aminopyridines/chemical synthesis , Carbamates/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Aminopyridines/pharmacology , Animals , Carbamates/pharmacology , Cholinesterase Inhibitors/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Male , Rats , Rats, Inbred StrainsABSTRACT
Tacrine (THA) is a potent cholinesterase inhibitor being studied for the treatment of Alzheimer's disease. The metabolism and excretion of THA were studied in rats following a single oral dose of 20 mg/kg of THA. The results show THA was extensively metabolized in rats after oral administration. Three major urinary metabolites were isolated by HPLC on a semi-prep analytical phenyl column, and subsequent purification of the individual fractions on a semi-prep analytical cyano column. The major metabolic pathways involve the hydroxylation of the saturated ring at positions 1, 2, and 4. The structures of the metabolites 9-amino-1,2,3,4-tetrahydroacridin-1-ol (1-OH-THA), 9-amino-1,2,3,4-tetrahydroacridin-2-ol (2-OH-THA), and 9-amino-1,2,3,4-tetrahydroacridin-4-ol (4-OH-THA) were determined by electron impact mass spectrometry and/or 1H-NMR, and compared with synthetic references. The urinary excretion of THA and metabolites was quantitated by HPLC with UV detection. About 60% of the oral dose was eliminated as total THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA over a 48-hr collection interval; and the non-conjugated THA and hydroxylated metabolites accounted for 45% of the dose.
Subject(s)
Tacrine/urine , Animals , Biotransformation , Chromatography, High Pressure Liquid , Hydroxylation , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Rats , Rats, Inbred Strains , Reference Standards , Spectrophotometry, Ultraviolet , Tacrine/chemistry , Tacrine/metabolismABSTRACT
The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease--the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (+/-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (+/-)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1 p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 microM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Aminoacridines/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Tacrine/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Cholinesterase Inhibitors/toxicity , Drug Evaluation , Drug Evaluation, Preclinical , Humans , Male , Memory/drug effects , Mice , Rats , Rats, Inbred Strains , Scopolamine/antagonists & inhibitors , Structure-Activity Relationship , Tacrine/analogs & derivatives , Tacrine/therapeutic use , Tacrine/toxicityABSTRACT
The indazole, benzisothiazole, and benzisothiazole 1,1-dioxide analogues of [[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid were synthesized and tested for diuretic activity in saline-loaded mice. Each analogue was found to be less active than the parent benzisoxazole: the diuretic activity followed the order O greater than S greater than N = SO2 in regard to the heteroatom in the 1-position of the ring.
Subject(s)
Diuretics/chemical synthesis , Isoxazoles , Oxazoles/chemical synthesis , Animals , Dogs , Mice , Natriuresis/drug effectsABSTRACT
A series of [(3-aryl-1,2-benzisoxazol-6-yl)oxy]acetic acids was synthesized and tested for diuretic activity in saline-loaded mice and in conscious, water-loaded dogs. The structural requirements for good diuretic activity in both mice and dogs were found to be very specific. In summary, the compounds with the best diuretic activity (13i, 13q, and 13ff) were substituted with a 2-fluorophenyl group at the 3 position and chlorine or bromine at the 7 position. Compound 13ff, [(7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy]acetic acid (HP 522), was found to be moderately uricosuric in chimpanzees and was selected for further development.
Subject(s)
Diuretics/chemical synthesis , Isoxazoles/chemical synthesis , Oxazoles/chemical synthesis , Animals , Diuretics/pharmacology , Dogs , Isoxazoles/pharmacology , Male , Mice , Structure-Activity Relationship , Uricosuric Agents/pharmacologyABSTRACT
The synthesis of 1'-[3-(4-fluorobenzyoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (2a) and eight halo and methoxy analogues is described. The compounds were generally more potent per os than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperido. 1'-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine] (2e) approached the per os potency of haloperidol in this test and was shown to be active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attrative as a potential neuroleptic.