British Biotech

A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies, which MMPs are suspected to be involved in. However, most of these, such as Marimastat (BB-2516), a broad spectrum MMP inhibitor, or trocade (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of... 

British Biotech has described co-crystal structures of both BB-3497 and actinonin bound in the active site of E. coli PDF [24]. The metal centre (Ni ) in both complexes adopts a pentacoordinate geometry, bound by the two oxygen atoms of the hydroxamate along with Cys-90, His-132 and His-136. This coordination pattern is consistent with the mechanism of de-formylation proposed by Becker et al. [56] and Jain et al. [67], in which a pentacoordinated metal centre stabilises the transition state during hydrolysis of the formamide bond. When compared to the co-crystal structure of a substrate hydrolysis product, Met-Ala-Ser, it is clear that the side chains of these two inhibitors bind into the active site pockets similarly to the substrate [56]. 

The discovery of BB-3497 was the result of screening a proprietary library for potential metalloenzyme inhibitors at the British Biotech Pharmaceutical Co. Ltd. [73]. This compound was originally prepared in a nonstereoselective manner and its stereochemistry was assigned on the basis of matrix metal-loprotease (MMP) inhibitory activity. The asymmetric synthesis of BB-3497 and the establishment of its stereochemistry by small-molecule X-ray crystallography was later reported by Pratt et al. [83]. Further structure-activity relationship studies of BB-3497 with respect to the modification of the P2 and P3 side chains [84] and metal binding group [85] were later reported by the scientists at British Biotech. These studies revealed that none of the... 

In the third randomized trial of an MMPI (British Biotech Study 145) (12), patients with locally advanced or metastatic gastric cancer were randomized in a double-blind fashion to a low dose (10 mg bid) of marimastat or matching placebo. Marimastat 10 mg po bid, which had inferior survival compared to the higher dose of marimastat, was presumably selected as the active control arm for this trial based on its superior tolerability compared to high-dose marimastat. Patients randomized to marimastat had a trend to better overall survival (167 d vs 135 d p = 0.07) at the protocol stipulated endpoint of the study, and this statistical trend strengthened with an additional 6 mo of follow up (p = 0.048). Nevertheless, patients randomized to marimastat 10 mg po bid had statistically superior progression-free survival compared to patients randomized to placebo (p = 0.027). Marimastat 25 mg po bid, which was the most efficacious dose in British Biotech Study 128, was not tested in Study 145. 

BB-10901/huN901-DMl a-CD56-DMl TAP (humanized by CDR grafting) SCLC British Biotech/ ImmunoGen In Phase I (UK) Phase MI (US) 42... 

British Biotech Pharmaceuticals Limited, Wat ling ton Road, Oxford, 0X4 5LY, U.K. 

CCL3 British Biotech II BB-10010 (protein) Cancer No efficacy... 

Matthew McCourt, phd British Biotech Pharmaceuticals Ltd., Oxford, UK... 

Martin 1993 (72) discard 1st (British Biotech, Abingdon, UK/R D Systems) (60-10650)... 

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