Robert M. DiPardo

Amiloride derived inhibitors of acid-sensing ion channel-3 (ASIC3).

A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.

Bradykinin B1 receptor antagonists : An α-hydroxy amide with an improved metabolism profile

A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.

Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3)

A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.

Hydroxy cycloalkyl fused pyridone carboxylic acid M1 positive allosteric modulators

Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.

Benzolactams as non-peptide cholecystokinin receptor ligands

A series of 1,3-substituted benzolactams are reported which are nonpeptidal receptor ligands of the peptide hormone cholecystokinin (CCK). These compounds are composites of potent, selective benzolactam CCK-A antagonists and unique structural elements which have been demonstrated to enhance the affinity of certain 1,4-benzodiazepine CCK-A antagonists for the CCK-B receptor.

A Second Generation of Non‐Peptide Cholecystokinin Receptor Antagonists and Their Possible Therapeutic Potential

The profile of an acidic series of benzodiazepine CCK-B receptor antagonists is described. The tetrazolyl urea derivative L-368,935 had high affinity (CCK-B IC50 0.1 nM) and was one of the most selective (CCK-B/CCK-A 10,000) CCK-B antagonists known. L-368,935 was a CCK-B antagonist with high affinity on the rat ventromedial hypothalamic slice preparation (Kb 0.6 nM) and also blocked pentagastrin-induced calcium mobilization in GH3 cells. L-368,935 had potent in vivo activity and antagonized pentagastrin-induced gastric acid secretion in the anesthetized rat and CCK-8S-induced aspartate release using microdialysis in the striatum of conscious rats. Activity within the central nervous system was confirmed by a mouse ex vivo binding assay and by direct measurement of the compound within the central nervous system using an HPLC assay. A second generation of CCK-B receptor antagonists such as L-368,935 will be important in determining the therapeutic potential of this class of compound in man.