2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

Scheme 22.
2.12. 2-ATs as tau fibrillization inhibitors
Two potential 2-ATs (75 and 76, Scheme 23), with a total structure of amino-N-cyclopropyl-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide, were identified as a novel class of tau fibrillization inhibitors by Ballatore and co-workers [82, 83]. Initially, the bicycle derivative 75 showed drug-like properties and reached significant concentrations in the mouse brain after an intravenous injection, but compound 75 has limited water solubility. In subsequent in vivo efficacy studies, the authors synthesized another novel series of 2-AT derivatives and evaluated their aqueous solubility and activities in a heparin-induced tau K18PL fibrillization assay. Among these derivatives, compound 76 displayed higher aqueous solubility and a higher unbound fraction in brain homogenates compared to compound 75; therefore, the possible dose-limiting toxicity of compound 76 was evaluated in wild type mice. An evaluation of brain levels of compound 76 after 3 days of dosing via drinking water at 50 mg/kg/day revealed total brain levels of 139 nM, with a calculated free compound level of 6.0 nM. Because of its good oral bioavailability and acceptable water solubility, compound 76 was suggested to be suitable for long-term in vivo testing. The key steps in the synthesis of 2-ATs 75 and 76 are described in Scheme 23.
Scheme 23.
2.13. Effect on the GABA_B receptor
Through chemical manipulation of the prototypes COR627 and COR628 (Fig. 8) [84], Mugnaini et al. identified a new family of positive allosteric modulators of the GABA_B receptor in 2013 [85]. Likewise, the pharmacological activities of 2-(acylamino)thiophene derivatives have been assessed both in vitro and in vivo. Towards hit-to-lead optimization, the 4-methylphenyl (77) and 4-chlorophenyl (78) (Scheme 24) analogues were selected from among the promising samples and used in the in vitro assay at 25 μM. Both compounds were equipotent and slightly more active than the unsubstituted phenyl derivative. These findings led to the hypothesis that the increased activity obtained with methyl- and chloro- substituents might be due to their steric, rather than electronic, effects. According to the results from in vivo experiments, pretreatment with ineffective doses of compounds 77-79 synergistically increased the sedative/hypnotic effect of a subthreshold dose of baclofen on mice. In addition, all three parameters of baclofen-induced sedation/hypnosis were markedly altered by pretreatment with the test compounds in a dose-dependent manner. Interestingly, the potentiating effect of compound 78 was specific for baclofen, because no dose altered the sedative/hypnotic effect of pentobarbital.