“…29 Among the prepared compounds, BMS-193884 (ET A K i ϭ 1.4 nM; ET B K i ϭ 18,700 nM) showed promising hemodynamic effects in a phase II clinical trial for congestive heart failure. [31][32][33] Similarly, chemical variations of the D 2 /D 3 non-selective benzamide sulpiride ( Figure 6.12 ) led to compound Do 897, a selective and potent D 3 receptor partial agonist. The bioavailability of this compound is 100% in rats and it exhibits oral activity already at a 3 μ M/kg dosing.…”
Section: E New Leads From Old Drugs: the Sosa Approachmentioning
“…29 Among the prepared compounds, BMS-193884 (ET A K i ϭ 1.4 nM; ET B K i ϭ 18,700 nM) showed promising hemodynamic effects in a phase II clinical trial for congestive heart failure. [31][32][33] Similarly, chemical variations of the D 2 /D 3 non-selective benzamide sulpiride ( Figure 6.12 ) led to compound Do 897, a selective and potent D 3 receptor partial agonist. The bioavailability of this compound is 100% in rats and it exhibits oral activity already at a 3 μ M/kg dosing.…”
Section: E New Leads From Old Drugs: the Sosa Approachmentioning
“…Three simple changes in the structure of minaprine (Fig. 5) like shifting of the methyl group from the 3-to the 4-position (Compound 1), substitution of the morpholine by a tropane (Compound 2), and introduction of an hydroxyl group in the ortho position of the phenyl ring (Compound 3) eliminated the dopaminergic and serotoninergic activities and improved the partial agonistic cholinergic activity of compound 3 [26][27][28]. The noteworthy result was the total abolition of initial activity of minaprine on the dopaminergic and serotoninergic transmission in the final compound 3.…”
Section: Conversion Of Antidepressant Minaprine To a Muscarinic M1 Partial Agonistsmentioning
The selective optimization of side activities (SOSA) approach appears to be a promising strategy for lead generation. In this approach old drugs are used to generate new hits or leads. The objective of SOSA is to prepare analogues of the hit molecule in order to transform the observed “side activity” into the main effect and to strongly reduce or abolish the initial pharmacological activity. The idea of taking a molecule with a primary activity in humans and then enhancing a secondary effect through structural changes describes the most common implementation of SOSA. An advantage to starting a drug discovery program with molecules that have already been tested in humans is that those molecules have already satisfied many safety criteria. Such molecules also likely have favourable pharmacokinetic profiles. In the present review different successful examples of SOSA switches are summarized. We hope that the present review will be useful for scientists working in the area of drug design and discovery.
“…In addition to reinforcing serotonergic and dopaminergic transmission, this amino-pyridazine possesses weak affinity for muscarinic M 1 , receptors (K i = 17 lM). Simple chemical variations allowed the dopaminergic and serotonergic activities to be abolished, and the cholinergic activity to be boosted to nanomolar concentrations [36][37][38]. …”
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