Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, an ETA selective endothelin antagonist.

Sitaxsentan (3, TBC11251) (Wu et al. J. Med. Chem. 1997, 40, 1690) is an orally active ET(A) selective endothelin antagonist that attenuates pulmonary vascular hypertension and cardiac hypertrophy in rats (Tilton et al. Pulm. Pharmacol. Ther. 2000, 13, 87). It has demonstrated efficacy in a phase II clinical trial for congestive heart failure (Givertz et al. Circulation 2000, 101, 2922). During the discovery of 3, we observed several structure-oral bioavailability relationships. To investigate whether there is any generality in these trends, we synthesized some similar pairs of compounds in the latest series (Wu et al. J. Med. Chem. 1999, 42, 4485) and evaluated their oral properties. In both series, an acyl group at the 2-position of the anilide of these thiophene sulfonamides improved oral bioavailability. As a result of this exercise, TBC3214 (17) was identified as a sitaxsentan follow-on candidate. It is very potent (IC(50) for ET(A) = 40 pM) and highly selective for ET(A) vs ET(B) receptors (400 000-fold), with a half-life of >4 h and oral bioavailability of 25% in rats, 42% in cats, and 70% in dogs.

Endothelin antagonists: substituted mesitylcarboxamides with high potency and selectivity for ET(A) receptors.

We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ET(A) selectivity by approximately 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has approximately 10-fold higher ET(A) binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.

Primary hyperparathyroidism in a New Zealand community: a review of 40 cases.

Forty cases of primary hyperparathyroidism presenting over a 15 year period, have been reviewed. The disease was equally prevalent in both sexes with highest incidence in the sixth decade. Most patients presented with renal colic or calculi (73 percent) and skeletal disease was found in only 13 percent. A single parathyroid adenoma was found in 32 cases and hyperplasia was diagnosed in only two cases. Follow-up questionnaires were sent to 32 patients, and in 27 of these a full clinical and laboratory assessment was undertaken. Of 26 patients with renal colic preoperatively only six continued to experience colic one year after parathyroid surgery. Thirty percent of all patients were hypertensive preoperatively, and in only two patients did blood pressure normalise after surgery. Fourteen of 27 patients followed-up were found to be hypertensive. A highly significant fall was noted in serum calcium, chloride, alkaline phosphatase and urine calcium excretion postoperatively. Recurrence of the disease was low and less than 8 percent in this series. The low incidence (1 per 10 000 population per year) suggests that primary hyperparathyroidism is under diagnosed in the Christchurch community.

Neurilemmoma of the Vagus Nerve in the Neck.

A case of neurilemmoma of the vagus nerve in the neck is described, in which excision with preservation of the nerve was possible. Attention is drawn to the typical clinical picture presented by these tumours. Recognition of this should make it possible to suspect the diagnosis preperatively and so greatly reduce the risks of operative damage to the vagus nerve.

Long-term hormonal secretion from the autotransplanted sheep pancreas.

Seventy-five duct-ligated pancreatic segmental autotransplants were made into bipedicled skin loops on the necks of merino ewes by vascular suture to the carotid artery and jugular vein; the in situ pancreatic remnants apparently continued to function normally. Thirty-seven were found to be active hormone secretors (secretion-rate responses to Na butyrate greater than 1 mU/min for insulin or 5 ng/min for glucagon) when first tested approximately 1 month after transplantation; 12 remained active at 1 year, 5 at 2 years, and 4 at 3 years. At first testing, the responses were (mean +/- standard errors): insulin, 12.3 +/- 2.52 mU/min; glucagon, 52.6 +/- 13.5 ng/min. It is concluded that this autotransplant can, on occasion, be relatively long-lived and that it is a useful model with which to study not only pancreatic physiology but also non-immunological factors involved in survival of endocrine function in pancreatic transplants.

Studies with the autotransplanted ovine pancreas: glucagon and insulin secretion.

Basic studies on the secretion of glucagon and insulin by the ovine pancreatic autotransplant in the neck are described. Of the 17 transplants in the series none failed to secrete glucagon and only three failed to secrete insulin in detectable amounts. The longest surviving transplant actively secreted both hormones 3 years after transplantation and five other transplants were functional and the animals healthy after 16 months. Exocrine secretion disappears shortly after transplantation. Sodium butyrate and alanine each promoted the secretion of both hormones by the transplant. Glucagon failed to promote insulin secretion by the transplant, although it apparently stimulated the ovine in situ pancreas. The immediate (presumably direct) effect of insulin was to inhibit transplant glucagon secretion. Hypoglycaemia induced by peripheral insulin administration failed to stimulate glucagon secretion by the transplant, although it did promote glucagon secretion by the ovine in situ pancreas. Heparin did not markedly suppress basal transplant secretion of either glucagon or insulin. Phasic response patterns occurred with both hormones during long butyrate perfusions, although first-phase responsiveness was not a constant feature. In one trial, first-phase responses fell off with repeated short butyrate infusions. Glucagon and insulin secretory patterns in response to butyrate were remarkably alike, suggesting a common mechanism. Loss of specific functions by the ovine pancreas after transplantation is discussed.

Inhibition of acid secretion and gastric lesions in rats by the prostanoid Ro 22-6923.

The synthetic prostanoid Ro 22-6923 was studied for its ability to inhibit gastric secretion and to protect the gastric mucosa against the injurious effects of stress, indomethacin and ethanol. Ro 22-6923 inhibited basal acid secretion when administered intragastrically or intraduodenally to animals with a gastric fistula. The pH of the gastric juice promptly increased and remained above 5 for 3 h after an intragastric dose of 10 micrograms/kg and the pH remained above 4 for more than 3 h after this dose given intraduodenally. The increase in pH was associated with reduction of acid concentration and H+ output. Ro 22-6923 inhibited histamine-stimulated gastric secretion in a perfused stomach preparation with an ED50 of 15 micrograms/kg compared to values of 43, 126 and 289 micrograms/kg for prostaglandin (PG)E2, ranitidine and cimetidine, respectively. The synthetic prostanoid protected the gastric mucosa from the injurious effects of stress (oral ED50 values of 0.2 and greater than 1.0 mg/kg for Ro 22-6923 and PGE2, respectively) and indomethacin (oral ED50 0.07 and 0.06 mg/kg for Ro 22-6923 and PGE2, respectively). Cimetidine and ranitidine, at high doses, were effective against the mucosal damage produced by stress (ED50 values greater than 100 mg/kg) and indomethacin (ED50 values greater than 10 mg/kg). Ro 22-6923, but not PGE2 or 16, 16-dimethyl PGE2, inhibited dibutyryl cyclic AMP-induced [14C]aminopyrine accumulation by isolated parietal cells, indicating that the prostanoid has a direct inhibitory effect on H+ secretion. The results on the antisecretory and cytoprotective properties of Ro 22-6923 suggest this drug could be potentially useful in the pharmacotherapy of peptic ulcer disease.