Joseph Cacciola

Rational design of boropeptide thrombin inhibitors: β,β-dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile

The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.

The synthesis of lysine α-ketoamide thrombin inhibitord via an epoxy amide ring opening

Abstract We describe a novel route for the preparation of substituted α-ketoamides of lysine. These compounds, due to the presence of an electrophilic carbonyl, display submicromolar activity toward the enzyme thrombin.

Synthesis of conformationally-restricted boropeptide thrombin inhibitors

Abstract A series of boropeptide thrombin inhibitors was prepared in which the P3 residues of 2 (Ac-( D )-Phe-Pro-boroLys-OH · HCl) and 3 (3-Phenylpropionyl-Pro-boroLys-OH · HCl) were replaced by conformationally-restricted, benzoic acid-derived residues 4 . The potent binding affinity of the resulting inhibitors such as 10 may be due in part to a unique mode of binding in the thrombin active site.

Preparation of meta-amidino-N,N-disubstituted anilines as potent inhibitors of coagulation factor Xa ☆

The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe a series of meta-amidino-N,N-disubstituted anilines as structurally simple and very potent inhibitors of factor Xa.

(N-acyl-N-alkyl)glycyl borolysine analogs: A new class of potent thrombin inhibitors

Abstract In this report the structure-activity relationships of a series of novel (N-acyl-N-alkyl)glycyl borolysine thrombin inhibitors are described. This work culminates in the discovery of (N-3-phenylpropanoyl-N-phenethyl)glycyl borolysine (12j), a potent, orally active inhibitor with a binding conformation in which the N-phenethyl group occupies the aryl binding pocket of thrombin.

Discovery of spirofused piperazine and diazepane amides as selective histamine-3 antagonists with in vivo efficacy in a mouse model of cognition.

A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

Synthesis and activity studies of conformationally restricted α-ketoamide factor Xa inhibitors

Abstract Conformationally restricted borolysine compounds containing a 2-(2-cyanophenylthio) benzoyl in the P3 position unexpectedly led to enhanced factor Xa inhibition. In an effort to improve both the potency and selectivity of this series by extending into the S′ domain, we have replaced the boronic acid with α-ketoamides, utilizing a novel process that was developed in our labs.