Mary F. Malley

Utilization of a nitrogen–sulfur nonbonding interaction in the design of new 2-aminothiazol-5-yl-pyrimidines as p38α MAP kinase inhibitors

The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.

Identification of 1-{2-[4-chloro-1′-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4′-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y1 antagonist as an antiplatelet agent

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.

Urea based CCR3 antagonists employing a tetrahydro-1,3-oxazin-2-one spacer.

Conformational restriction of open chain analogs with a more polar tetrahydro-1,3-oxazin-2-one spacer led to the identification of potent urea-based CCR3 antagonists that exhibited excellent selectivity over binding to CYP2D6. The in vitro binding and eosinophil shape change data are presented. Compound 19b exhibited similar selectivity and potency to our development candidate BMS-639623.

Molecular design and structure-activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.

An unexpected by-product obtained during the preparation of technetium(III) boronic acid adducts of dioximes. The single crystal structure of TcCl(DMG)2(BDI)BEt (DMG=dimethylglyoxime, BDI=butane-2, 3-dione imine-oxime)

Abstract An unusual Tc(III) boron-capped imine-oxime complex has been isolated from the reaction of 99TcCl3(CH3CN)(PPh3)2, dimethyl glyoxime (DMG) and ethyl boronic acid (EtB(OH)2). A single crystal X-ray structure analysis of this molecule 99TcCl(DMG)2(BDI)BEt (BDI=butane-2, 3-dione imine-oxime) shows it to be seven coordinate: TcClC14H25N6O5B, a=9.073(2), b=23.686(5), c=19.539(6) A; β=93.77(2)°, P21/n, Z=8. Its structure is very similar to that of previously reported Tc(III) complexes 99TcCl(dioxime)3BR, except that one dioxime ligand on the molecule has been reduced to an imineoxime.

Studies towards understanding the mechanism of the unusual rearrangement of certain 5-propargyloxyindoles

Abstract A mechanism of the rearrangement of 5-propargyloxyindoles is proposed and supported by the formation of a novel tetracyclic indole derivative 12 as the major product in the cyclization of 5-propargyloxytryptophol 10 .

Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor.

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.

Cannabinoid CB1 receptor ligand binding and function examined through mutagenesis studies of F200 and S383

The cannabinoid CB(1) G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptors three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB(1) receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB(1) receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB(1) receptor ligands.

Conformationally constrained calcium channel blockers: novel mimics of 1-benzazepin-2-ones.

In order to test a hypothesis that the seven-membered ring of the benzothiazepinone (diltiazem) and benzazepinone calcium channel blockers serves primarily to orient two critical pharmacophores in space, a series of novel, conformationally constrained bicyclo[2.2.2]octyl amines 3 which severely restrict the relative orientations available to the amine and methoxyphenyl groups was prepared. All compounds which positioned the pharmacophores on the same face of the molecule demonstrated vasorelaxant activity and affinity for the diltiazem receptor equal to or greater than racemic diltiazem 1 or the corresponding benzazepione 2. In addition, compound 3d was equipotent to (+)-diltiazem in its ability to reduce ischemic/reperfusion injury in an in vitro model of myocardial ischemia. However, 3d is significantly less cardiodepressive at an equivalent antiischemic dose. Therefore, the original receptor binding hypothesis led to the design and synthesis of novel calcium channel blockers with unique biological properties.