Jeffery S Carter

The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life.

In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t(1/2)=360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2)=34 h.

The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part III: The three microdose candidates

In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data. The challenge of a surprisingly long half-life (t(1/2)=360 h) of the first clinical candidate 1 and human t(1/2) had been difficult to predict based on allometric scaling for this class of highly ppb compounds. We used a microdose strategy which led to the discovery of clinical agents 18c-(S), 29b-(S), and 34b-(S) with human half-life of 57, 13, and 11 h.

The novel benzopyran class of selective cyclooxygenase-2 inhibitors-part I: The first clinical candidate

In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. 5c-(S) (SD-8381) was advanced into clinical studies due to its superior in vivo potency. The high plasma protein binding (>99% bound) of 5c-(S) has resulted in a surprisingly long human half life t(1/2)=360 h.

Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors

A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compounds unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.

To Market, To Market—2003

Publisher Summary This chapter discusses 27 drugs which were manufactured in the year 2003 related to cardiovascular, anticancer, allergic and respiratory diseases, male erectile dysfunction, and attention deficit/hyperactivity disorder. The cardiovascular sector had four new drugs entering the market in 2003: Crestor™ (rosuvastatin), Livalo ® (pitavastatin), Calblock ® (azelnidipine), a gradual-onset, long-acting calcium antagonist, and Inspra™(eplerenone). The anticancer field saw the introduction of three new drugs: Velcade ® (bortezomib), Erbitux ® (cetuximab), and Bexxar ® (tositumomab). In the field of allergic and respiratory diseases, two new entities reached the market: Rupafin ® (rupatidine fumarate) and Xolair ® (omalizumab). In the area of endocrine and metabolic diseases, three new drugs appeared on the market: Somavert ® (pegvisomant) and Aldurazyme ® (laronidase). Zavesca™ (miglustat), a glucosylceramide synthase inhibitor, was introduced as the first orally active treatment for type 1 Gauchers disease. Following the success of Viagra ® (sildenafil) in the treatment of male erectile dysfunction (ED), two new phosphodiesterase type 5 (PDE5) inhibitors were launched: Cialis™ (tadalafil) and Levitra™ (vardenafil). The CNS area was represented by the launch of Strattera™ (atomoxetine). Two new biologic immunosuppressive agents were also launched: Amevive ® (alefacept) and Raptiva™ (efalizumab). A significant NBE introduced last year was Humira™ (adalimumab). The other notable NBE launched in 2003 was FluMist™ (influenza virus live).

Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors.

Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.