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Biomedical subjects

R Woltmann

Publications and source records attributed to R Woltmann.

5 recordsLinked to original sources
PubMed1997

Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.

Administration, Oral↗
PubMed1997

Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Animals↗
PubMed1987

Examination of diltiazem for preservation of myocardial function after brief regional ischemia.

Diltiazem (750 micrograms/kg plus 600 micrograms/kg/h X 1 h, i.v.) and vehicle were examined in open-chest anesthetized dogs subjected to 15 min of occlusion of the left circumflex coronary artery (LCCA). Regional segment lengths in myocardium supplied by the LCCA and by the left anterior descending coronary (LAD) were measured with piezoelectric crystals implanted in the subendocardium. Diltiazem decreased heart rate and mean arterial pressure, and increased coronary blood flow, determined with an electromagnetic flowmeter. Vehicle had no significant effects. Occlusion of the LCCA increased end diastolic segment length (EDL), and produced akinesis or paradoxical systolic lengthening: diltiazem -2.5 +/- 2.7% and vehicle 0.0 +/- 1.2% segmental shortening (SS). EDL and SS in the LAD zone showed small increases. After 15 min, the LCCA was reperfused and recovery of SS was followed for 3 h. Significantly greater recovery of SS was observed with diltiazem compared to vehicle throughout reperfusion: at 5 min, diltiazem 105 +/- 22% and vehicle 43 +/- 7% and at 180 min, diltiazem 73 +/- 0% and vehicle 33 +/- 8% of baseline SS. The LCCA and LAD zones both responded to isoproterenol 0.3 microgram/kg given 2.5 h after reperfusion. During the isoproterenol challenge SS for LCCA in the diltiazem group (122 +/- 21%) was not different than that of vehicle (99 +/- 15% of baseline). Calcium entry blockade with diltiazem resulted in improved myocardial function during reperfusion. The stunned myocardium showed significant stimulation of shortening by isoproterenol in both groups.

Animals↗