5-HT6 receptors are expressed in the brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. We report the development of a novel, aqueous-soluble, safe, BBB penetrant potent series of small molecule antagonists of 5-HT6 receptors in a series of new Dimebon analogs. Recently Dimebon was reported to have met all five efficacy endpoints in a one-year randomized, double-blind, placebo-controlled phase II study of ∼200 patients with mild to moderate Alzheimer's Disease. We were the first to show that Dimebon is a potent 5-HT6 antagonist (Ki = 70 nM) and selected this drug as a starting point for the design of novel drug-like chemotypes. The design, synthesis, and SAR studies included tri- and bicyclic “core” and/or “decoration” variations of chemical structure in several consecutive iterations. Cognition disorders perhaps due to their unique intricacy have not benefited from rational single-targeted drug design. In response to this challenge we have selected a few key biotargets for specific modulation. The “constellation” of 5-HT6, 5-HT2C, AChE, Ca L-channel, NMDA, etc. was chosen as desirable for inhibition (antagonism), and hERG, 5-HT2B (“black holes”) were identified as undesirable. SAR data will be demonstrated around the lead series to illustrate the improvements in targeting affinities at multiple biomolecules. Hit-to-lead optimization of this series has led to the discovery of the advanced lead compounds possessing the desired fingerprint along with a promising in vivo profile. The lead compounds demonstrated an excellent PK-PD correlation. Administering these agents has significantly reversed scopolamine- and MK801-induced deficit in a rodent novel object recognition paradigm and passive avoidance test. The compounds have also reversed the deficit in water maze spatial learning compared to vehicle-treated scopolamine-matched controls. These studies provide further support for the potential therapeutic utility of 5-HT6 receptor antagonists possessing a desired fingerprint in disorders characterized by cognitive deficits such as Alzheimer's Disease.