The 5-HT6 receptor (5-HT6R) is a G-protein coupled receptor positively coupled to adenylate cyclase primarily localized within the central nervous system, particularly in brain regions associated with cognition. Antagonism of the 5-HT6R has been reported to modulate the release of multiple neurotransmitters including elevating extracellular levels of glutamate and acetylcholine in regions associated with cognitive function such as the cerebral cortex and hippocampal formation. Accumulating preclinical and clinical data suggest that 5-HT6R antagonists may function to improve cognitive performance and therefore serve as effective treatment options for Alzheimer's disease. SAM-531 (WAY-262531) is a new chemical entity that is a selective full antagonist at the 5-HT6R. Here we describe the pre-clinical profile of SAM-531 in support of its clinical development as a treatment for Alzheimer's disease. SAM-531 was characterized in vitro in multiple assays evaluating binding affinity, functional activity and receptor selectivity. In vivo characterization of SAM-531 consisted of an evaluation of the effect of treatment on brain neurochemistry using in vivo microdialysis as well as tests of rodent cognitive function such as contextual fear conditioning and novel object recognition. Cognitive testing was performed in assays utilizing both pharmacological and non-pharmacological deficit states. SAM-531 is a potent and selective full antagonist at the human 5-HT6R (Ki = 1.0 nM; IC50 = 10 nM). In rats, oral administration of SAM-531 caused significant increases in extracellular levels of glutamate and acetylcholine in the dorsal hippocampus. Treatment with SAM-531 blocked a scopolamine-induced deficit in a hippocampal-dependent learning and memory task, contextual fear conditioning. In addition, SAM-531 treatment blocked both glutmatergic- (MK-801) and cholinergic-mediated (scopolamine) deficits in recognition memory. Furthermore, treatment with SAM-531 enhanced retention of recognition memory when measured 48 hours after training, a time at which memory no longer can be measured in vehicle-treated animals. SAM-531 is a potent, selective and orally bioavailable 5-HT6R antagonist which modulates neurotransmitters associated with learning and memory and is active in multiple assays of cognitive dysfunction in the rodent. These studies provide pre-clinical support for the further development of the 5-HT6R antagonist SAM-531 as a potential treatment for Alzheimer's disease.

1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.

An efficient route to the biologically active naphthyl benzofuran derivative is described. The synthesis highlights a regioselective Suzuki coupling of a benzofuran and a dibromo substituted naphthalene. The scope of regioselective Suzuki coupling has been investigated.

Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to and inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, and pharmacokinetic attributes led to identification of tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to clinical trials.

Compounds of formula (I): (see formula) wherein: R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, or perfluoroalkyl C1-C3 alkyl, wherein the alkyl groups and cycloalkyl may be optionally substituted by halogen, -CN, C1-C6 alkoxy, -OH, -NH2, or -NO2; R2 is hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, thienyl, CH2-thienyl, furanyl, CH2furanilo, oxazoyl, CH2-oxazoyl, phenyl, benzyl, or CH2-naphthyl; in the alkyl group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzyl and naphthyl may be optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 perfluoroalkyl, C1-C3, -O-C3-perfluoroalquiloC1, -S-C1-C3 perfluoroalkyl, C1-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C (O) CH3, -C (O) OR7, -C (O ) NH2, -S (O) 2CH2, -OH, -NH2, or -NO2; R3 is hydrogen, halogen, C1-C6, C1-C3 perfluoroalkyl, C1-C6, C3-C6 cycloalkyl, or -CH2-C3-C6 cycloalkyl ci; R4 is C3-C8 cycloalkyl C3-C6, -CH2-C3-C6 cycloalkyl, thienyl, CH2-thienyl, furanyl, oxazoyl, phenyl, benzo [b] furan-2-yl, benzo [b] thien-2- yl, benzo [1, 3] dioxol-5-yl, or naphthyl; in the alkyl group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl, and naphthyl may be optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 perfluoroalkyl, C1- C3, -O-C1-C3 perfluoroalkyl, -S-C1-C3 perfluoroalkyl, C1-C3 alkoxy, -OCHF2, -C (O) CH3, -C (O) OR7, -C (O) NH2, -S ( O) 2CH3, -OH, -NH2, or -NO2; R5 is C1-C8, cycloalkyl C3-C6, -CH2-C3-C6 cycloalkyl, pyridinyl, -CH2-pyridinyl, thienyl, CH2-thienyl, furanyl, CH2-furanyl, oxazoyl, CH2-oxazoyl, phenyl, benzyl, benzo [b] furan-2-yl, benzo [b] thien-2-yl, benzo [1, 3] dioxol-5-yl, naphthyl, CH2-naphthyl, 9H yl-fluoren-1-9H-fluoren-4 -yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl, 9-fluorenone-2-yl, 9-fluorenone-4-yl, or CH2-9H-fluoren-9-yl; in the alkyl group and the rings of the cycloalkyl, pyridinyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, benzofuranyl, benzothienyl, naphthyl, fluorenyl, and fluorenone may be optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, -O-C1-C3 perfluoroalkyl, -S-C1-C3 perfluoroalkyl, C1C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C (O ) CH3, -C (O) OR7, -C (O) NH2, -S (O) 2CH3, -OH, -NH2, -NO2, or phenoxy, the phenoxy group optionally substituted by 1 to 3 groups selected independently being further from halogen, C1-C3 perfluoroalkyl or C1-C3; R6 is hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, pyridyl, thienyl, CH2-thienyl, furanyl, CH2-furanyl, oxazoyl, CH2-oxazoyl, phenyl, benzyl, benzo [b] furan-2-yl, benzo [b] thien-2-yl, benzo [1, 3] dioxol-5ilo, CH2-1-naphthyl, or CH2-2-naphthyl; inthe alkyl group and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, benzofuranyl, benzothienyl, and naphthyl may be optionally substituted by 1 to 3 groups independently selected from halogen, C1-C3 perfluoroalkyl C1 -C3, -O-perfluoroalkyl C1C3, -S-C1-C3 perfluoroalkyl, C1-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C (O) CH3, -C (O) OR7, -C (O) NH2, -S (O) 2CH3, -OH, -NH2, or -NO2; or R5 and R6 taken together may be C3-C6cycloalkyl, 3-yl-indan-1-, 1, 2, 3, 4 yl-tetrahydronaphthalen-1-, chroman-4-yl, 4H-chromen-4-yl, thiochroman -4-yl, 9H-fluoren-9-yl, 9, 9H-xanthene-9-yl, 9Htioxanten-yl-9, 6, 7, 8, 9-tetrahydro-5H-benzocyclohepten-yl 10-dihidroantracen-9 -5-yl, or 10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl, where these groups may optionally be substituted by 1 to 3 groups independently selected from halogen, C1-C3 , C1-C3 perfluoroalkyl, -O-C1-C3 perfluoroalkyl, -S-C1-C3 perfluoroalkyl, C1-C3 alkoxy, -OCHF2, -CN, -COOH, -CH2CO2H, -C (O) CH3, -C (O ) OR7, -C (O) NH2, -S (O) 2CH3, -OH, -NH2, or -NO2; and R7 is C1-C6, C3-C6, -CH2-C3-C6, or benzyl.

A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC(50) = 0.14 microM)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED(50) = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC(50) = 0.10 microM) which shows excellent in vivo efficacy (ED(50) = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4-(1, 1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED(20) = 100 mg/kg; selectivity: MAP ED(20)/bladder ED(50) = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.