The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alpha MAP kinase inhibitor

A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.     

Skin Collagen and Thickness in Simple Obesity

The effects of stretching of the skin on its collagen content and thickness have been studied in a group of subjects with chronic obesity. Despite the increase in skin surface a normal skin thickness, collagen content, and density were maintained. It is concluded that the skin stretching induced by prolonged obesity led to hypertrophy of collagen and that this had maintained both skin thickness and collagen content. It is not known whether this is due to enhanced synthesis or decreased degradation.     

Sebum Excretion in Acromegaly

The sebum excretion rate (S.E.R.) was measured in 20 patients with acromegaly. Eleven were untreated at the time of the measurement and nine had previously undergone surgical hypophysectomy or had received pituitary irradiation by yttrium-90 or radiotherapy. In five patients the S.E.R. was measured before and after such treatment. The mean S.E.R. in the untreated acromegalics was much greater than in a normal population and decreased significantly after successful pituitary ablation. No significant decrease in mean S.E.R. occurred in the group of patients with a poor clinical response to ablation. The correlations between S.E.R. and log serum growth hormone, plasma 11-hydroxycorticosteroid levels, and heel-pad thickness were significant, but there was no significant correlation between S.E.R. and serum protein-bound iodine levels. This suggests that the changes in S.E.R. were due to pituitary ablation but could not necessarily be attributed solely to changes in growth hormone, thyroid-stimulating hormone, or adrenocorticotrophic hormone. The association between the clinical state of the acromegaly and the S.E.R. was better than the association between acromegaly and serum growth hormone. We conclude that the S.E.R. is a useful addition to the clinical and endocrinological data used in assessing acromegaly.     

Osteoporosis,Skin Collagen,and Androgen

Total skin collagen was found to be decreased in untreated patients with osteoporosis, particularly women, but increased after treatment with androgens in women. Decreased body collagen may possibly be a primary defect in osteoporosis, while androgens may increase total skin collagen.     

Generalised tissue abnormality of aryl hydrocarbon hydroxylase in psoriasis.

Microsomal aryl hydrocarbon hydroxylase (AHH) activity and inducibility were measured in jejunal mucosa, liver, and lesion-free epidermis of patients with psoriasis. In all three tissues AHH activity and inducibility were less than in controls. This demonstration of a generalised enzymatic abnormality in the tissues of patients with psoriasis is in keeping with the suggestion that it may be close to the underlying genetic defect.