A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11β-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10-30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ∼ 35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

A growing body of evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates conversion of glucocorticoids from inactive to active forms. 11β-HSD1 knock-out mice have improved cognition and the non-selective inhibitor carbenoxolone improved verbal memory in elderly men. Taken together, these data suggest that 11β-HSD1 inhibition may be a potential new therapy for cognitive deficits associated with AD. We characterized two novel 11β-HSD1 inhibitors, A-918446 and A-801195. Mice were treated with A-918446 in diet for 18 days, tested in a 24-hour inhibitory avoidance (IA) test that measures memory consolidation/recall and then sacrificed to examine cAMP response element binding protein (CREB) phosphorylation in the cingulate cortex. To investigate the efficacy of acute administration, mice received A-918446 one hour before training in the IA test or before tissue collection. In rats, A-801195 was administered one hour before testing in a social recognition assay that measures short-term memory. Inhibition of brain cortisol production by A-801195 one hour post acute dosing was examined using an ex-vivo assay. Cortical and hippocampal acetylcholine release was measured via in vivo microdialysis in rats receiving acute A-801195. Dietary A-918446 (10 or 100 mg/kg/day for 18 days) improved memory consolidation and increased CREB phosphorylation in the cingulate cortex (100 mg/kg/day dose only) in mice. Furthermore, acute A-918446 (0.3-30 mg/kg) induced a dose-dependent improvement in memory consolidation/recall and increased cortical CREB phosphorylation. In rats, acute A-801195 (10 and 30 mg/kg, but not 3 mg/kg) significantly improved short-term memory. Efficacious doses of A-801195 (10 and 30 mg/kg) acutely inhibited brain cortisol production while a non-efficacious dose (3 mg/kg) did not. The cognitive improvement induced by 11β -HSD1 inhibitors is not likely a result of alterations to the cholinergic system, as no changes in cortical or hippocampal acetylcholine levels were observed in rats after treatment with A-801195 (30 mg/kg). These studies demonstrate that 11β-HSD1 inhibitors induce cognitive enhancement in two species and multiple cognitive domains through a novel, non-cholinergic mechanism, thereby suggesting that 11β-HSD1 inhibitors may be useful for the treatment of cognitive dysfunction associated with AD.

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.

Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.

A novel class of adamantane ethers 11 beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynarnic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed. (c) 2006 Elsevier Ltd. All rights reserved.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Dexfenfluramine (DEX) and sibutramine (SIB) are effective antiobesity agents. Their effects on weight control and hormone profile have not been previously studied in diet-switched diet-induced obese (DIO) mice, in which treatment is initiated upon cessation of a low-fat diet and resumption of a high-fat diet. Furthermore, their effects on circulating ghrelin in obese humans or in animal models of obesity have not yet been reported. Male C57BI/6J DIO mice after 16 wk on a high-fat diet (HF, 60 kcal% fat) were switched to a low-fat diet (LF, 10 kcal% fat) for 50 d. HF diet resumed concurrently with treatment for 28 d with DEX 3 and 10 mg/kg, twice a day (BID); SIB 5 mg/kg BID; or vehicle. Rapid weight regain ensued in vehicle-treated DIO mice. DEX or SIB treatment significantly blunted the body weight gain. Caloric intake was decreased acutely by DEX or SIB vs vehicle during the first 2 d treatment, but returned to control after 5 d. At the end of study, epididymal fat weight and whole body fat mass determined by DEXA scan were decreased by DEX 10 mg/kg, and whole body lean mass decreased with DEX 3 mg/kg treatment. Circulating ghrelin on d 28 was increased with either DEX 3 or 10 mg/kg treatment, while growth hormone and insulin were decreased. Leptin was also decreased in the DEX 10 mg/kg group. SIB did not significantly affect fat mass, ghrelin, growth hormone, insulin, or leptin. mice chronically fed LF diet maintained a lower caloric intake, gained less weight and fat mass than diet-switched mice, and had higher ghrelin and lower insulin and leptin. in summary, weight regain in diet-switched DIO mice is delayed with either DEX or SIB treatment. DEX treatment of diet-switched DIO mice decreased growth hormone, insulin, leptin, fat mass, lean mass, and increased ghrelin, while SIB only decreased body weight.

Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.

Structure-activity relationships were investigated on the tricyclic dihydropyridine ( DHP) K-ATP openers 9-(3-bromo-4-fluorophenyl)-5,9- dihydro-3H, 4H-2,6-dioxa-4-azacyclopenta[ b] naphthalene-1,8-dione ( 6) and 10( 3-bromo-4-fluorophenyl)-9,10-dihydro-1H, 8H-2,7-dioxa-9-azaanthracene-4,5-dione ( 65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk-cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.