Pfizer clinical candidates

The key cis stereochemical relationship is created by an alkylation reaction that sets a tram stereochemical relationship, which is then reversed in the subsequent ringopening and closing sequence. Although this route replaced both the quinuclidine and the benzhydryl group of CP-96,345 (2), it produced a very potent NKi receptor antagonist, CP-99,994 (17). This simplified structure then served as a starting point for many variants, including clinical candidates CP-122,721 (18)5 (Pfizer) and GR-205,171 (19)6 (GSK). 

The initial in vitro activity of several of the standard NK] receptor antagonists compared with aprepitant is given in Table 1. The three clinical candidates from Pfizer, GSK, and Merck stand out as the most potent compounds in this regard. 

The chloracetic methine linked to the azetidinone nitrogen, which in compound 304 reacted as an electrophile, upon deprotonation can react as a nucleophile in other cyclization strategies. Very recently the conversion of trithiocarbonates 308a, b to penem 309 (a precursor of Pfizer s clinical candid-... 

Scheme 14.40 Pfizer CaSR antagonist clinical candidates.

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

The combinatorial decoration or derivatization of existing natural products is a popular method for library creation. Among targets for such exercises are the alkaloids yohimbine and scopolamine, terpenoids and steroids, and the heterocyclic peptide antibiotic GE-2270A (Figure 11). In the latter case, combinatorial variation was instrumental in the discovery of a developmental candidate now in clinical trials at Vicuron. Pfizer, the world s largest pharmaceutical company, recently acquired Vicuron for the sum of 1.9 billion, a mark of approval for natural product-based combinatorial chemistry. 

Sildenafil citrate originally entered development as a candidate for the treatment of angina, but the early clinical results were disappointing. In 1994 Pfizer ran a small phase Ila trial with 12 patients suffering from male erectile dysfunction. Ten of those patients showed major improvements in their erections. Suddenly the project changed overnight. Sildenafil citrate had been the lowest-priority project in the Pfizer development portfolio, and now it became one of the highest. The medicinal... 

For example, in one 30-day period in the late summer of 2006 no fewer than four small companies, Icagen, Corcept, SGX, and Adolor, lost 73%, 56%, 41%, and 45% of their stock values, respectively, in one single day because of bad news on late-stage clinical trials. In contrast, Pfizer stock lost 10.6% of its value (still about 19 billion ) after the company announced that it was discontinuing clinical trials on its most promising candidate, torcetrapib, for safety reasons. 

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