Hans Petersen

N″-cyano-N-4-pyridyl-N′-1,2,2-trimethylpropylguanidine, monohydrate (P 1134): A new, potent vasodilator

N″-cyano-N-4-pyridyl-N′-1,2,2-trimethylpropylguanidine, monohydrate (P 1134) is a new agent which induces a marked and sustained hypotensive response in normotensive and renal, neurogenic, and spontaneously hypertensive rats, as well as in normotensive and renal hypertensive dogs. The overall potency of this compound is 2–3 times greater than that of hydralazine. The fall of blood pressure is accompanied by an increase in heart rate and cardiac output and a decrease in total peripheral resistance. The hypotensive effect appears to be due primarily to a direct relaxant effect on vascular smooth muscle.

Synthesis of novel GABA uptake inhibitors. Part 6 : Preparation and evaluation of N-Ω asymmetrically substituted nipecotic acid derivatives

In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates.

The synthesis of novel GABA uptake inhibitors. Part 2. Synthesis of 5-hydroxytiagabine, a human metabolite of the GABA reuptake inhibitor tiagabine

Abstract (R)-1-(4-(2,5-Dihydro-3-methyl-5-oxothien-2-ylidene)-4-(3-methyl-2-thienyl)butyl)-3-piperidinecarboxylic acid (5-hydroxytiagabine) 13, has been prepared in 8 steps from 2-bromo-3-methylthiophene 3. Key steps are Grignard reactions, displacement of heteroaromatic chlorine with methoxy, and simultaneously demethylation and opening of a hydroxymethylcyclopropane with bromotrimethylsilane. An alternative approach involving acylation of 2-lithio-3-methylthiophene 17a was found less satisfying. A metalloporphyrin assisted hydroxylation of tiagabine 1 also yielded the target metabolite. The structure of 5-hydroxytiagabine was confirmed by NMR-data including COSY, ROESY, HMQC and HMBC experiments.

Synthesis and in vitro characterization of new growth hormone secretagogues derived from ipamorelin with dipeptidomimetic N-terminals

The structural requirements for N-terminal features for the minimal structure of growth hormone secretagogues derived from ipamorelin are investigated. It is found, that incorporation of nonpolar peptidomimetic amino acids at the N-terminal can replace the Aib-His moiety and lead to compounds with high in vitro potency with respect to their growth hormone secretagogue properties. New unnatural amino acids with double bonds, ether-linkages, and 1,3-phenylene-moieties in the backbone proved to be valuable dipeptidomimetics. Using them, growth hormone secretagogues with high potencies were obtained.

Efficient syntheses of regioisomers of tiagabine

Epilepsy is a disorder characterized by recurrent spontaneous electrical discharges within the brain which are manifested by clinical seizures. Four million patients in the USA are afflicted with this ailment; 20% of these have seizures which cannot be controlled sufficiently with existing medications to permit normal activities of everyday life. Epileptic seizures can be classified as primary epilepsies (35%) and partial epilepsies (65%). Primary epilepsies (generalized convulsions) can be controlled with valproate (Depakote), carbamazepine (Tegretol), phenytoin (Dilantin), or phenobarbitol. Most of the partial epilepsies have resisted control with chemotherapeutic agents. Current targets for therapeutic intervention with respect to epilepsy are (i) blocking of receptors of excitatory amino acids, (ii) modulating membrane ion channels (sodium and calcium) involved in neuronal membrane excitability and (iii) enhancing the neurotransmittory effect of gamma-aminobutyric acid (GABA)