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A E Weber

Publications and source records attributed to A E Weber.

41 records · Page 3Linked to original sources
PubMed1991

Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

Amino Acid Sequence↗
PubMed1989

Synthesis, biological activity, and conformational analysis of (2S,3R,4S)-MeBmt1-cyclosporin, a novel 1-position epimer of cyclosporin A.

Cyclosporin A (CsA, 1), an immunosuppressive cyclic undecapeptide, contains a unique amino acid, (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine (MeBmt), that appears to be critically involved in the biological activity of CsA. In order to further explore the effect that structural elements in MeBmt have on the conformation and biological activity of CsA, the 4-epimer of MeBmt [(4S)-MeBmt, 2] and the corresponding CsA analogue [(4S)-MeBmt1-CsA, 3] have been synthesized. Biological assay using concanavalin A stimulated thymocytes indicated that (4S)-MeBmt1-CsA (3) has only 2-4% immunosuppressive activity relative to CsA. The NMR analysis by 1D and 2D NMR methods establishes the conformation of 3, of which the 33-membered cyclic peptide ring system in chloroform is very similar to that of CsA. However, the NMR analysis also reveals that the 1-position side chain orientation in (4S)-MeBmt1-CsA (3) is very different from that of CsA. Specifically, the (4S)-MeBmt alpha,beta-torsion angle (chi 1) has been rotated approximately 120 degrees relative to that of CsA, and the orientation of the butenyl side chain relative to the 33-membered peptide backbond is different. The orientation of the (4S)-MeBmt side chain is consistent with the possible conformations calculated for (4S)-MeBmt1-CsA (3) by using molecular mechanics (in vacuo) calculations. The conformational analysis suggests that the loss of biological activity for 3 results from an altered conformation of the 1-position side chain relative to the peptide backbond due to the changed chirality at C4 of MeBmt.

Chemical Phenomena↗
PubMedDate not supplied

Morbidity and mortality related to human immunodeficiency virus in Canadian men and women, 1987-94.

OBJECTIVE: To assess the impact of HIV/AIDS on hospitalization and mortality patterns in Canada. METHODS: Hospitalizations and deaths due to HIV/AIDS were compared with select causes of morbidity and mortality among men and women across provinces, regions and select cities between 1987-94. Patterns of hospitalization and mortality were characterized by calculating age-specific, standardized rates, rate ratios and potential years of life lost before 65 years. RESULTS: A total of 28,462 hospitalizations (26,153 in men and 2,309 in women) and 8,739 deaths (8,192 in men and 547 in women) were attributed to HIV/AIDS during the study period. Rates of HIV/AIDS hospitalization were highest for men in Ontario, Quebec and British Columbia, and in Montreal, Toronto and Vancouver; while among women they were highest in Quebec and in Montreal, Toronto and Vancouver. Mortality rates followed a pattern similar to the rates found for hospitalization. CONCLUSIONS: Our analysis reveals the considerable impact of HIV/AIDS on patterns of morbidity and mortality in Canada.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Cholesterol granuloma of the petrous apex: MR and CT evaluation.

We reviewed the clinical, CT, and MR findings in seven consecutive patients who had a total of nine cholesterol granulomas. Preoperative MR scans were available for five of the seven patients; two patients were studied with MR after treatment only (one had a recurrent lesion and the other was asymptomatic at the time of study). Preoperative CT scans were available for all patients, except one patient who was examined after developing a symptomatic recurrence. All lesions were detected by both imaging methods. Seven preoperative lesions (five patients) and one symptomatic recurrence (one patient) demonstrated increased signal intensity of both T1- and T2-weighted MR images. Three surgically drained lesions (three patients) showed a marked reduction in signal intensity on T1-weighted images. Pre- and postoperative lesions had different patterns of signal intensity on the chemical-shift images, which were obtained in two instances. The MR appearance of cholesterol granuloma differs from that of most other lesions that occur in the petrous apex. CT did not differentiate between pre- and postoperative lesions in all cases, while MR demonstrated a dramatic change on T1-weighted images and chemical-shift studies. Our findings indicate that MR is more specific than CT in suggesting the correct diagnosis of cholesterol granuloma and that MR appears to be the technique of choice in the follow-up of previously treated patients.

Adult↗