Thomas J. Lanza

Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding Ki of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma Cmax of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30–40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

Anti-obesity efficacy of a novel cannabinoid-1 receptor inverse agonist MK-0364 in rodents

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding Ki of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma Cmax of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30–40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

The discovery of sulfonylated dipeptides as Potent VLA-4 antagonists

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

Total synthesis of 1-156,602, a novel cyclic hexadepsipeptide antibiotic

Abstract The total synthesis of the naturally occurring cyclic hexadepsipeptide antibiotic L-156,602 ( 1 ) is described.

6-substituted indoles from o-halonitrobenzenes

Abstract o-Chloro- and o-bromonitrobenzenes are efficiently converted to 6-substituted indoles in a four step synthesis, proceeding through o-trimethylsilylethynylnitrobenzenes, o-nitrophenylacetaldehyde dimethylacetals and o-aminophenylacetaldehyde dimethylacetals as intermediates. o-Chloro- and o-bromonitrobenzenes are efficiently converted to 6-substituted indoles in a four step synthesis. R = CO2Me(H), COPh, Ph, CF3 and Me.

Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity.

Extensive structure-activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution.

Specific and dual antagonists of α4β1 and α4β7 integrins

N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the α4β1 integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of α4β1 and α4β7, and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for α4β1 and α4β7 is proposed to explain the structure–activity relationship.

Deprotection of N-tert-butoxycarbonyl (Boc) groups in the presence of tert-butyl esters

Abstract Deprotection of Boc groups in the presence of tert -butyl esters was achieved by using concentrated H 2 SO 4 (1.5–3.0 equiv.) in t BuOAc or MeSO 3 H (1.5–3.0 equiv.) in t BuOAc:CH 2 Cl 2 (4:1 v/v). The yields ranged from 70 to 100% for a variety of amino acid and dipeptide substrates.

Phosphinic acid inhibitors of matrix metalloproteinases

Abstract The matrix metalloproteinase stromelysin-1 (MMP-3) is inhibited more strongly by peptidyl phosphinic acid 7 than by its corresponding phosphonamidate and phosphonate analogs. Extending a benzyl group at P′ 1 to a phenylethyl group in 8 further increases the potency (K i = 1.4 nM). Enhanced potency with an extended substituent into the P 3 region was observed.