Philip M. Sher

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.

BMS-187257, a potent, selective, and novel heterocyclic β3 adrenergic receptor agonist

Abstract Novel heterocyclic β 3 adrenergic receptor agonists 2 were prepared and evaluated for their ability to bind to human β 1 , β 2 , and β 3 adrenergic receptors. Stimulatory effects on the β 3 adrenergic receptor were also measured. BMS-187257 ( 4b ) was found to be a potent and selective β 3 agonist.

Carboxyl-promoted enhancement of selectivity for the β3 adrenergic receptor. Negative charge of the sulfonic acid BMS-187413 introduces-β3 binding selectivity

Abstract Carboxyl and other negatively charged groups were found to be most effective at producing human β3 adrenergic receptor binding selectivity in 1 (BRL 37344) and related compounds. The sulfonic acid analog 7 (BMS-187413) is a novel and potent β3 adrenergic agonist that binds selectively, and thus has an in vitro profile that compares favorably with that of BRL 37344.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

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.

Thromboxane receptor antagonist BMS-180291: A new pre-clinical lead

Abstract The synthesis and initial pharmacology of interphenylene 7-oxabicyclo[2.2.1]heptane oxazole thromboxane (TxA2) receptor antagonist BMS-180291 is described. BMS-180291 has been characterized as an orally bioavailable, potent and selective TxA2 antagonist with a long duration of action.

A practical synthesis of ATB-[2-3H] BMPA, a photolabelling reagent for exofacial glucose transporters

Major improvements in the efficiency of ATB-[2-3H]BMPA synthesis were achieved by using 1,3-dichloro-2-propanone O-benzyloxime (6) as the linking reagent.

Interphenylene 7-oxabicyclo[2.2.1]heptanes. SQ33,961: a new potent, long-acting thromboxane antagonist ☆

Abstract The synthesis and initial biological evaluation of a novel series of chiral interphenylene 7-oxabicyclo-[2.2.1]heptane TxA2 antagonists with 4-amido oxazole omega chains is described. Within this series SQ 33,961 has been identified as a highly potent TxA2 antagonist with an exceptionally long in vivo duration of action.

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.