Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists.

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2.

Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.

Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Addition of benzylic and allylic organozinc and Grignard reagents to resin-bound imines to provide alpha-branched secondary amines bearing a wide variety of functional groups. Utility in the synthesis of beta-3 adrenergic receptor agonists.

Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.